kristoff@GENBANK.BIO.NET (Dave Kristofferson) (08/11/90)
REQUESTS FOR APPLICATIONS: RFA
RFA: HL-90-12-H
MECHANISMS OF DAMAGE CAUSED BY CARDIOPULMONARY BYPASS
P.T. 34; K.W. 0715040, 1002004, 0765035
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Letter of Intent Receipt Date: October 15, 1990
Application Receipt Date: December 3, 1990
INTRODUCTION
The National Heart, Lung, and Blood Institute (NHLBI) invites
applications for grants to support basic research, studies
with animal models, and clinical investigation targeted
toward: 1) obtaining a better understanding of the
mechanisms of multisystem damage seen with cardiopulmonary
bypass and by the often associated technique of profoundly
hypothermic total circulatory arrest, and into the
particular susceptibility to this damage of the very young
and the elderly; and 2) developing methods of preventing or
attenuating this damage.
Cardiopulmonary bypass is required for cardiac surgery,
extracorporeal membrane oxygenation, and percutaneously
established circulatory support, resulting in over 375,000
uses annually in the United States alone. It results in
considerable pulmonary, cardiac, neurologic, and renal
dysfunction, generalized edema, and diffuse bleeding, which
cause important morbidity and mortality, especially in the
very young, the elderly, and the very ill. Both neonates
and patients over 70 years of age routinely require 48 hours,
and occasionally 3 to 6 weeks, of tracheal intubation after
open heart surgery because of pulmonary dysfunction.
The age distribution of patients receiving cardiopulmonary
bypass has changed markedly in recent years. Ten years ago
1% of cardiopulmonary bypass patients were 1 year old or
less; now this number is 10-20%. Ten years ago the average
age of a patient having coronary artery bypass graft surgery
was 55-60; now it is close to 70. With this shift in the
proportion of very young (<1 year) and of elderly (>70
years) patients receiving cardiopulmonary bypass, certain
problems have become more prominent. Whereas diffuse
bleeding is seen in about 2% of patients overall, it is
about twice as frequent in the very young. Neurologic
dysfunction after cardiac surgery is seen in about 2% of
patients overall, but in the very young and the elderly the
incidence is about 10%. Peritoneal or hemodialysis is
required in about 1% of patients overall; but in the very
young and the elderly it occurs in about 5-10%. Overall
mortality is about 8%, but in the very young and the elderly
it approximates 15%. Of these, 95% of the very young and
65% of the elderly die from cardiac dysfunction. Pulmonary
dysfunction after bypass is probably present in all patients
regardless of age. These findings suggest a particular
susceptibility of the cardiac, pulmonary, and hemostatic
systems in the very young and of the central nervous system
and kidneys in both the very young and the elderly.
One of every 20 adults requires a cardiac support device
after cardiac surgery. All patients have increased total
body and extracellular fluid as well as an easily
demonstrable hemorrhagic diathesis after cardiopulmonary
bypass, and these may be fatal, particularly in infants,
the elderly, and the very ill. This all results in
potentially preventable loss of life, prolonged intensive
care with its high costs, prolonged hospitalization with
economic disadvantages, and delayed patient rehabilitation.
The complex defensive mechanisms of inflammation are
activated during the extracorporeal circulation of blood for
cardiopulmonary bypass, and have been shown to be highly
related to the resultant damage. Periods of global cardiac,
and at times total systemic, ischemia are required for most
cardiac operations, and even with currently used protective
measures produce an additive inflammatory reaction.
BACKGROUND
Throughout evolution, circulating blood has traveled only in
endothelial lined channels. With the advent of
cardiopulmonary bypass for cardiac surgery and other
purposes, circulating blood began to be passed through
foreign pathways. Considerable evidence indicates that this
contact with artificial surfaces activates the multiple
cascades of inflammation, the complement pathway, and the
hemostatic mechanism.
When open heart operations were first performed in the mid-
1950's, patients developed unexplained bleeding, morbidity,
and mortality unlike anything which surgeons had previously
encountered. The idea soon developed that the large surface
area of a nonbiologic oxygenator was primarily at fault, and
that poor-risk patients and very old patients were
particularly likely to have this kind of morbidity and
mortality. The duration of cardiopulmonary bypass was soon
recognized as an important contribution to bleeding,
morbidity, and mortality. As operations became more complex
and very long-term cardiopulmonary bypass support began to
be used, thrombosis also became evident.
Cohnheim began to develop current concepts of inflammation a
hundred years ago. As stated by Houck in 1979, "The subtle
kaleidoscopic cascades of interdigitated events which
constitute the reaction of tissues to injury over a variable
time scale is obviously mediated, modulated and
orchestrated by a wide variety of chemical messengers which
influence and determine vascular, extracellular and cellular
sequelae." Cardiopulmonary bypass initiates the activation
and release of such messengers, resulting in a generalized
inflammatory response. Injury begins the moment blood
contacts foreign surfaces, and rapid activation of the
various pathways begins. Although these reactions are
discussed separately for purposes of clarity, the responses
are in fact highly interrelated and the entire process may
be initiated by the almost immediate activation of Factor
XII.
The humoral cascades of inflammation are now known to
involve at least the complement, kallikrein, coagulation,
and fibrinolytic cascades; the cellular components involve
at least leukocytes, platelets, and endothelial cells, with
amplification by the arachidonic acid pathway. In addition,
cardiopulmonary bypass is the most powerful known stimulator
of catecholamine response. Cardiopulmonary bypass is
associated with massive activation of the complement
cascade, and this is reduced by hypothermia and
hemodilution. Multiple interactions during and soon after
cardiopulmonary bypass have been demonstrated between
complement activation, neutrophil activation, pulmonary,
cardiac, and renal dysfunction, and survival. The
kallikrein cascade is activated, with the finding of
elevated levels of bradykinin during and soon after
cardiopulmonary bypass. However, the relation of this and
neutrophil activation to the demonstrated increase in
microvascular permeability produced by cardiopulmonary
bypass is uncertain. Likewise, the relation of the
vasodilatory effect of bradykinin to the decreased systemic
vascular resistance that characterizes cardiopulmonary
bypass and the early period thereafter is not clear.
The coagulation cascade is strongly activated during
cardiopulmonary bypass, although gross clotting is prevented
by heparinization. Platelets are activated during
cardiopulmonary bypass, adhere to synthetic surfaces, lose
their ability to respond to soluble agonists, change shape,
release granular contents, form aggregates, and contribute
to thrombus formation. Importantly, platelet receptors for
epinephrine and fibrinogen decrease during cardiopulmonary
bypass. These and other platelet responses and interactions
result in an increased bleeding time and play a major role
in perioperative bleeding. In addition, activation of the
fibrinolytic cascade during cardiopulmonary bypass may play
a role in perioperative bleeding. Activation of the
arachidonic acid pathway has been demonstrated by the
finding of increased levels of the inactive degradation
product of the potent platelet aggregating agent thromboxane
A2 which is especially marked in infants and results at
least in part from the action of activated component C5a.
There is also a striking increase in levels of the powerful
inhibitor of platelet aggregation, prostacyclin
(prostaglandin I2;PGI2), during cardiopulmonary bypass.
The commonly observed pulmonary dysfunction may be related
to the complement-dependent activation of neutrophils and
monocytes during cardiopulmonary bypass, sequestration of
activated neutrophils in the lung, and oxygen-free radical
generation. All patients develop at least mild, and some
severe, pulmonary edema after cardiopulmonary bypass. The
relation between neutrophil activation, the complement and
kallikrein-induced increase in microvascular permeability,
and the whole body increase in water (edema) during and
after cardiopulmonary bypass remains uncertain.
Interleukin-1 production by monocytes is markedly enhanced
within a few hours of cardiopulmonary bypass, and the ratio
of OKT4+ to OKT8+ cells is altered, particularly in patients
who are very ill prior to surgery. It is clear from this
brief review that many aspects of mechanisms of inflammation
are affected by cardiopulmonary bypass.
In addition, hypothermia and periods of total circulatory
arrest importantly affect these pathways. Reduction and
reversal of body temperature, by changing the solubility of
gases in blood, may stimulate the formation of microbubbles.
Air inadvertently entering the cardiopulmonary bypass
circuit is a potential cause of air embolism which may cause
clinically significant cerebral or coronary ischemia. The
contribution of protamine sulfate administration (to
neutralize heparin) and of autologous blood cell salvage,
washing, and transfusion, to the damaging effects of
cardiopulmonary bypass have not been well defined.
Furthermore, certain organ systems have been shown to
manifest "selective vulnerability" to the damaging effects
of cardiopulmonary bypass, hypothermia, and total
circulatory arrest. For example, the time interval between
onset of ischemia and necrosis is greater in skeletal than
in cardiac muscle and is greater in spinal cord than in
cortical neurons. Some of these areas of selective
vulnerability show an age dependency. When total
circulatory arrest results in neurologic damage, in adults
this is almost always manifested at least by intellectual
deficits, but in infants, by seizures and choreoathetotic
movements. It has recently been shown that following total
circulatory arrest, levels of glutamate, an excitatory
neurotransmitter which can lead to metabolic requirements in
excess of substrate supply, increase in areas with a high
concentration of N-methyl-D-aspartate (NMDA) receptors. A
transient increase in the expression of NMDA receptors in
certain of the basal ganglia has been observed in neonatal
and young subjects.
OBJECTIVES AND SCOPE
Applicants are encouraged to develop their own approaches
within their areas of expertise to investigating fundamental
mechanisms of the complex humoral, cellular, and other
responses to cardiopulmonary bypass; to developing methods
of preventing or minimizing these responses; or to exploring
and testing in vivo newly developed methods of management.
Cardiopulmonary bypass is a versatile experimental model for
studying fundamental mechanisms since its duration is
controllable and the magnitude of its effect can be varied
by its duration and other conditions. Promising areas of
investigation include, but are not limited to:
o Investigation of the interactions of the various cascades
mentioned in producing the humoral, cellular, and
clinical results observed following bypass; investigation
of a possible single initiating event, for example,
activation of Factor XII
o Investigation of differences (compared with the adult age
group) in the function of cardiac, immunologic, hemostatic,
neurologic, renal, and other systems in the very young and
the elderly, which could explain the different
susceptibility of these groups to the problems they
experience following bypass
o Investigation of the primacy of neutrophil activation, or
its dependence on the humoral cascades or platelet
activation
o Investigation of the contribution of blood-foreign surface
interactions, heparin-protamine interactions, blood
component transfusions, profound hypothermia, and other
aspects of cardiopulmonary bypass to the results observed
o Modulation of the humoral and cellular effector systems of
the hemostatic, complement, or inflammatory pathways by
pharmacologic mediators capable of reversibly downregulating
these systems
o Reversible blockage of NMDA receptors in the basal ganglia
of neonates and infants prior to cardiopulmonary bypass, as
a means of protecting against important ischemic damage
during profoundly hypothermic cardiopulmonary bypass and
total circulatory arrest.
Applicants are encouraged to examine one or more components
or conditions used during cardiopulmonary bypass, and to
study the interactions of the activated pathways. Studies
of the possible causes of the relation of the problems
observed to age, either in the very young or the elderly or
both, are encouraged. Such studies could involve
biochemical, physiological, pathological, or other
observations in patients or experimental animals.
This RFA is designed to address the problems seen with
conventional cardiopulmonary bypass; however, applications
dealing with extracorporeal membrane oxygenation (ECMO) or
percutaneously established circulatory support will not be
excluded. Clinical studies may be included if they form
logical extension of a basic investigation proposed.
In any studies involving human subjects, women and minority
individuals should be included in the study population;
otherwise a clear rationale for their exclusion must be
provided in the application. Minority institutions are
encouraged to apply, and other institutions are encouraged
to established collaborative arrangements with minority
institutions.
EXCLUSIONS
No support will be provided under this Request for
Applications (RFA) mechanism for
large clinical trials. Support for development of
techniques or devices alone will not be provided. In
general, funds will not be provided for the purchase and
installation of expensive, new equipment. Institute staff
should be consulted if an applicant has questions regarding
these limitations.
MECHANISM OF SUPPORT
The support mechanism for this program will be the
traditional, individual research grant. Although
approximately $1.2 million for this program is included in
the financial plans for fiscal year 1991, award of grants
pursuant to this RFA is contingent upon receipt of funds for
this purpose. It is anticipated that four to six grants will
be awarded under this program. The specific amount to be
funded, however, will depend on the merit and scope of the
applications received and the availability of funds. Since
a variety of approaches would represent valid responses
to this announcement, it is anticipated that there will be a
range of costs among individual grants awarded. While
multidisciplinary approaches are encouraged, it is not the
intent of this announcement to solicit applications for
large studies encompassing a variety of independent
projects, i.e., program projects. If collaborative
arrangements involve sub-contracts with other institutions,
the NHLBI Grants Operations Branch should be consulted
regarding procedures to be followed (tel: 301-496-7255).
Upon initiation of the program, the Division of Heart and
Vascular Diseases and the Division of Blood Diseases and
Resources will jointly sponsor periodic meetings to
encourage exchange of information among investigators who
participate in this program. In the budget for the grant
application, applicants should request ADDITIONAL TRAVEL
FUNDS for a one-day meeting each year, most likely to be
held in Bethesda, Maryland. Applicants should also include
a statement in their applications indicating their
willingness to participate in these meetings.
Applicants, who will plan and execute their own research
programs, are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed
research project. Up to FIVE YEARS of support may be
requested. At the end of the official award period, renewal
applications may be submitted for peer review and
competition for support through the regular grant program of
the National Institutes of Health (NIH). It is anticipated
that support for the present program will begin on August 1,
1991. Administrative adjustments in project period and/or
amount of support may be required at the time of the award.
All current policies and requirements that govern the
research grant programs of the NIH will apply to grants
awarded under this RFA. Awards under this announcement to
foreign institutions will be made only for research of very
unusual merit, need, and promise, and in accordance with
Public Health Service policy governing such awards.
REVIEW PROCEDURES AND CRITERIA
Review Method: Upon receipt, applications will be reviewed
for their responsiveness to the objectives of this RFA. If
an application is judged unresponsive, the applicant will be
contacted and given the opportunity to withdraw the
application, or have it considered for the regular NIH grant
program.
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this
RFA that is essentially identical to one that has already been
reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
Those
applications which are judged to be responsive will be
reviewed for scientific and technical merit by an invited
review group convened by the Division of Extramural Affairs,
NHLBI, composed of mostly nonfederally employed reviewers
with expertise that will include cardiac surgery,
cardiology, pediatrics, immunology, hematology, rheology and
fluid mechanics, materials science, surface chemistry, and
biostatistics. Applications will be reviewed in competition
with each other on a nation-wide basis. This RFA
solicitation is a single competition and has one specific
deadline for receipt of applications.
Review Criteria: The factors to be considered in the
evaluation of scientific merit of each application will be
similar to those used in the review of traditional research
project grant applications, including:
o the novelty, originality, and feasibility of the approach,
and the adequacy of the experimental design
o the competence of the principal investigator and
collaborator to accomplish the proposed research, and the
commitment and time they will devote to this project
o the suitability of the facilities to perform the proposed
research, including laboratories, instrumentation, and
data management systems
o of the appropriateness of the requested budget for the
work proposed.
METHOD OF APPLICATION
Letter of intent: Prospective applicants are asked to
submit a letter of intent to apply to this RFA. This letter
should include the names of any participating institutions
and all investigators, together with a descriptive title.
Such a letter of intent is not binding and it will not enter
into the review of any application subsequently submitted,
nor is it a necessary requirement for application. Letters
of intent are requested solely for planning purposes. The
NHLBI Staff will not provide responses to such letters.
Letters of intent to apply to this RFA should be received no
later than October 15, 1990, and should be addressed to:
Dr. Charles L. Turbyfill
Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
Westwood Building, Room 553
Bethesda, MD 20892
Format for Applications: Submit applications on form PHS-
398 (revised 10/88), the application form for the
traditional NIH research project grant. Copies of this form
are available in the applicant institution's office of
sponsored research, or may be obtained from the following:
Office of Grants Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
Bethesda, MD 20892
Use the conventional format for research project grant
applications and ensure that the points identified in the
section above on "Review Procedures and Criteria" are
fulfilled. To identify the application as a response to
this RFA, CHECK "YES" on item 2 of page 1 of the application
and enter the title "Mechanisms of Damage Caused by
Cardiopulmonary Bypass" and the RFA number HL-90-12-H in
the space provided.
THE RFA LABEL FOUND IN THE FORM PHS 398 APPLICATION KIT MUST
BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL
COMPLETED APPLICATION FORM PHS 348. FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION
SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR
REVIEW.
Application Procedure: Send or deliver the completed,
signed application and four (4) completed photocopies of it
to the following, making sure that the original application
with the RFA label attached is on top:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER "LETTER OF INTENT".
IT IS IMPORTANT TO SEND TWO COPIES AT THE SAME TIME AS THE
ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF
RESEARCH GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT
THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS
RFA.
Applications must be received by December 3, 1990. An
application not received by this date will be considered
ineligible.
Timetable:
Letter of Intent: October 15, 1990
Application Receipt Date: December 3, 1990
Review by National Heart, Lung,
and Blood Advisory Council: May 1991
Anticipated Award Date: August 1, 1991
Inquiries regarding this announcement may be directed to the
following:
Paul Didisheim, MD Diane Lucas, PhD
Devices and Technology Branch Blood Diseases Branch
Division of Heart and Vascular Division of Blood Diseases
Diseases, NHLBI and Resources, NHLBI
Federal Building, Room 312 Federal Building, Room 5A12
NIH NIH
Bethesda, MD 20892 Bethesda, MD 20892
Telephone: (301) 496-1586 Telephone: (301) 496-5911
Fax: (301) 480-6282 Fax: (301) 496-9940
This program is described in the Catalog of Federal
Domestic Assistance number 13.837, Heart and Vascular
Diseases. Awards will be made under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR
Part 74. This program is not subject to the
intergovernmental review requirements of Executive Order
12372, or to Health Systems Agency Review.
REQUEST FOR RESEARCH PROJECT GRANT APPLICATIONS: RFA
INDEX MARKERS FOR A FRAMEWORK LINKAGE MAP OF THE HUMAN GENOME
RFA AVAILABLE: HG-90-02
P.T. 34; K.W. 1215018, 0760002, 1002058
National Center For Human Genome Research
Letter of Intent Receipt Date: September 10, 1990
Application Receipt Date: October 16, 1990
The National Center for Human Genome Research (NCHGR) invites
applications for assistance awards for research into the isolation
of highly polymorphic genetic linkage markers and their use for the
development of a framework linkage map of the human genome.
This program is described in the Catalog of Federal Domestic
Assistance No. 13.172. Awards will be made under the authority of
the Public Health Service Act, Sections 301 (Public Law 78-410, as
amended 42 U.S.C. 241) and administered under PHS grants policies
and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This
program is not subject to the intergovernmental review requirement
of Executive Order 12373 or to Health System Agency review.
BACKGROUND
The NCHGR sponsors basic and applied research concerned with the
development and application of new technologies for the
characterization and analysis of the human genome and the genomes
of important model organisms. The activities encompassed by the
NCHGR program include genetic and physical mapping, DNA sequencing,
and informatics related to mapping and sequencing. The NCHGR, in
conjunction with the Department of Energy, recently formulated a
five-year plan that identified areas where further research,
including new technology development, is needed before the
characterization of the human and other genomes can proceed to the
degree envisioned.
The five-year plan, "Understanding Our Genetic Inheritance," is
available from the address given below. In it, the goal for
linkage mapping is the development of a two to five centimorgan
(cM) linkage map of the human genome (i.e., a map in which DNA
markers are spaced, on average, two cM apart and with no gaps
between adjacent markers greater than five cM). The NIH has
previously solicited applications for research projects to develop
such a high-resolution linkage map under a series of program
announcements. The NCHGR will continue to accept applications for
such projects in response to the most recent program announcement,
"Mapping, DNA Sequencing, and Technology Development in Support of
the Human Genome Program" (NIH Guide for Grants and Contracts; Vol.
19, No. 28, July 27, 1990).
As a result of discussions within the scientific community, it has
recently become clear that the development of a high-resolution linkage
map of the human genome would be greatly abetted by the
construction of a "framework map" consisting of a set of "index"
markers, each of which being much more informative than typical DNA
markers. A framework map consisting of an ordered set of highly
informative markers could be used to rapidly localize any new gene
or marker to a particular interval; efforts to map the marker to a
finer resolution could then be restricted to that interval.
Because of its expediency in the rapid localization of new entities
(markers, genes, traits, etc.) to a small chromosomal region, a
framework map of highly informative markers would be employed both
by scientists involved in the localization and identification of
specific genes, such as those associated with particular diseases
or syndromes, and those engaged in the construction of high-
resolution linkage maps.
Approximately 2,000 polymorphic human markers have been isolated to
date. Many of these are restriction fragment length polymorphisms
(RFLP's). More recently, a variety of markers that can be
identified and characterized using the polymerase chain reaction
(PCR) has been developed. However, only 10% or fewer of these
existing markers are informative enough to be useful as index
markers on a framework map. This number is not adequate to develop
a maximally useful framework map. Furthermore, the distribution of
the known highly polymorphic markers is not random within the
genome. Thus, any attempt to construct a framework map with only
currently available markers would produce a map in which some
regions would contain a number of tightly clustered index markers
while other regions would have few or no index markers. These
latter regions, or gaps, would be large enough and frequent enough
that such a map would not be readily usable for rapid gene
localization.
It has been estimated that a useful framework map would consist of
markers whose heterozygosity is 70% or better, with an average
spacing of ten to fifteen cM between markers.
However, the precise number of index markers needed per chromosome
and the size of the intervals defined by each pair of index markers
will vary, as the suitable spacing between adjacent markers will
depend on the specific characteristics of the individual markers.
The more highly polymorphic a marker is, the farther it can be from
the adjacent markers and still be useful for the kinds of mapping
for which a framework map is intended, i.e., markers with a
heterozygosity of 95% can be farther apart than markers with a
heterozygosity of 70%. The utility of the framework map will be
further enhanced if each marker is identified by a "sequence-tagged
site" (STS), a DNA sequence that is unique in the human genome and
is identifiable with the polymerase chain reaction (Olson et al.
[1989] Science, Vol. 245, p. 1434).
Given the usefulness that a framework linkage map of the human
genome would have for laying the foundation for building a high-
resolution map and for mapping and isolating functional genes, the
NCHGR is interested in supporting research projects designed to
isolate new highly polymorphic markers and assemble them into a
framework map for each human chromosome.
RESEARCH GOALS
This RFA is intended to solicit applications for research projects
designed to develop a framework linkage map of one or more human
chromosomes as described above. Issues that are appropriately
addressed in applications responding to this RFA include:
o identification and collection of existing markers;
o isolation of new index markers;
o mapping of index markers;
o the relationship between the degree of polymorphism and
spacing of index markers on the framework map;
o criteria to be used for determining when the framework
map is complete;
o error analysis and quality control issues associated with
mapping.
Each applicant responding to this solicitation should identify one
(or more) human chromosome(s) for which a framework map will be
developed and indicate the anticipated time needed to complete it.
It is not necessary that all of the index markers be isolated or
mapped in the applicant's own laboratory; collaboration with other
laboratories for the collection and mapping of index markers is
encouraged. Although the time required to complete a framework map
will vary by chromosome, it is estimated that it should be possible
to complete a framework map of the entire human genome in two to
three years.
MATERIALS AND DATA RELEASE
The purpose of this Request for Applications (RFA) is to
encourage the construction of a framework map of
particularly useful linkage markers for each human
chromosome. It would be of most benefit to the entire
scientific community for the maps, the markers comprising
them, and the data supporting the localization of the
markers to become available as rapidly as possible. The
policy of the U.S. Public Health Service (PHS) states that
"when resources are developed with PHS funds and the
associated research findings have been published...it is
essential that they be made readily available for research
purposes to the scientific community." In many cases,
however, the interpretation of this policy is problematic,
e.g., in cases in which only selected data are published.
This is an area of active discussion within the scientific
community. Currently, there appears to be a consensus that
material resources and certain unpublished data should be
available for distribution at a reasonable time after they
are developed. In this context, the NCHGR is interested in
the applicant's discussion of the issues involved in making
index markers and supporting data available and in plans for
doing so.
In considering these issues and developing such plans, applicants
should be aware that, in order to assist investigators in
distributing markers and mapping data, the NCHGR will identify and
support an appropriate repository and/or database that is qualified
and suitable for collecting and distributing the index markers and
supporting mapping data. The NCHGR will also support any
additional costs required by investigators for deposition of
markers and data in this repository/database.
To assist communication among investigators developing framework
maps of individual chromosomes, semi-annual meetings of all
grantees receiving funds under this RFA are planned.
MECHANISM OF SUPPORT
Support for this program will be through research project grants
(R01). The award period will be three years. Support for grants
under this RFA is contingent upon the appropriation of funds for
this purpose. It is anticipated that three million dollars will be
awarded during fiscal year 1991, although the number of awards is
contingent upon the quality and scope of the applications received.
Between awards made under this RFA and grants already funded by the
NCHGR, it is anticipated that sufficient resources will be provided
to develop a framework map of each human chromosome.
REVIEW PROCEDURES
Applications submitted in response to this RFA will be reviewed in
accordance with the normal NIH peer review procedures.
Applications will first be reviewed by NCHGR staff for
responsiveness. Those that are deemed non-responsive will be
returned to the applicant. If a large number of applications is
received, there will be a preliminary peer review to identify the
most meritorious ones. Applications that are deemed non-competitive
by this peer review will receive only a brief critique and will not
be reviewed further. The remaining applications will be reviewed
for scientific merit by an initial review group (IRG) organized for
this purpose by the Office of Scientific Review, NCHGR. A second-
level review will be conducted by a national advisory council.
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this
RFA that is essentially identical to one that has already been
reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
Criteria that will be used to assess the scientific merit of
applications are:
o Overall scientific and technical merit of the research;
o Training, research track record, and dedication of the
principal investigator;
o Potential for achieving the goals of this RFA;
o Adequacy of the available facilities;
o Provision for the protection of human subjects and the
humane care of animals; and
o Appropriateness of the requested budget for the work
proposed.
AWARD CRITERIA
Funding decisions will be based on the recommendations of the IRG
and the advisory council regarding the scientific merit and program
relevance of the proposed research. It is expected that no more
than one award will be made for the framework map of each human
chromosome. The adequacy of the proposed plans for public access
to materials and data generated during the course of research
supported in response to this RFA will also be considered before an
award is made.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent by
September 10, 1990. This letter should include a brief
descriptive title, the names of key investigators, and the names
and addresses of other participating institutions.
The letter of intent is requested in order to
provide an indication of the number and scope of applications to be
reviewed. The letter of intent does not commit the sender to
submit an application, nor is it a requirement for submission of an
application. Please send letters of intent to:
Mark S. Guyer, Ph.D.
Assistant Director for Program Coordination
National Center for Human Genome Research
Room 605, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
E-mail: gy4@nihcu.bitnet
gy4@cu.nih.gov
APPLICATION PROCEDURES
Applications should be submitted using the form PHS 398 (rev.
10/88). The RFA label available in the revised application kit
MUST be affixed to the bottom of the face page. Failure to use
this label could result in delayed processing of the application
such that it might not reach the review committee in time.
Application kits are available in the business or grants office at
most academic or research institutions, or from the Division of
Research Grants, National Institutes of Health. Applications will
be accepted in accordance with the following schedule:
Receipt of applications October 16, 1990
Initial review November/December 1990
Council review January 1991
Earliest award date April 1, 1991
It is essential that the applicant type "A Framework Linkage Map
of the Human Genome" and the RFA number HG-90-02 on line 2 of the
face page of the application form. The original and four copies of
the application should be submitted to the following office:
Grant Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892**
To expedite the review process, it is important to submit two
additional copies of the application directly to:
Office of Scientific Review
National Center for Human Genome Research
Room 604, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
It is strongly recommended that potential applicants contact NCHGR
staff to discuss research objectives. Any additional information
required can be obtained from:
Mark S. Guyer, Ph.D.
Assistant Director for Program Coordination
National Center for Human Genome Research
Room 605, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
Telephone: (301) 496-0844
E-mail: gy4@nihcu.bitnet
gy4@cu.nih.gov
REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS:
RFA: HD-90-12
NATIONAL COOPERATIVE PROGRAM ON CULTURE CONDITIONS FOR
NON-HUMAN IN VITRO FERTILIZATION AND PREIMPLANTATION
DEVELOPMENT
P.T. 34; K.W. 0413002, 1002017, 0780000
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
Application Receipt Date: November 20, 1990
OVERVIEW
The National Institute of Child Health and Human Development
(NICHD) invites applications from investigators willing to
participate, with the assistance of the NICHD under cooperative
agreements, in an ongoing multisite Cooperative Program designed
to establish improved culture conditions for non-human in vitro
fertilization and preimplantation embryo development. It is
anticipated that a multi-species approach will be continued
as a central feature of the Program. New findings obtained
from research on one species could be rapidly tested in
other species owing to the lines of communication between
cooperating sites.
The Institute staff Research Coordinator will cooperate with
the Principal Investigators of the selected sites in the
determination of approaches and protocol designs, planning,
evaluation, and publication of the research, and serve as
coordinator, facilitator, and partner in the research. It is
expected that protocols will change as new information is
gathered and shared.
A general overview of Program phases follows. These phases
are not necessarily sequential since the Program will
evolve, but can serve as a guide for applicants:
PHASE I (one month) - Determination, by consensus, of
experimental approaches, design of protocol(s), methods of
standardization of experiments between sites, determinations
of experimental end points and methods of evaluation;
methods of standardization of reagents and other culture
conditions; determination of statistical methods;
PHASE II (47 months) - Testing of culture media
formulations, gas phases and culture vessels for non-human
in vitro fertilization and preimplantation development;
PHASE III (12 months) - Analysis and dissemination of
results to be done as various segments of the research are
completed.
These Phases are intended to be flexible, recognizing that
the Program is likely to undergo continuous evolution.
Applicants should provide an in-depth justification and
description of how they might approach and conduct the
study, including their own capabilities and any special
considerations peculiar to their organism(s) of choice.
The deadline for applications is November 20, 1990.
Applications received after this date will not be
considered. Only applicant institutions in the United
States will be eligible.
BACKGROUND
The goal of this Cooperative Program is to improve the
culture conditions for non-human in vitro fertilization and
preimplantation development that are necessary for basic and
applied reproductive research on mammalian gametes and
preimplantation development. This basic and applied
research has implications for several critical problems that
lie at the center of mammalian reproductive biology.
Included among these problems are:
1 The mechanisms of fertilization and implantation, the
prevention of polyspermy, contraception, the causes and
alleviation of infertility, and genetic assessment;
2 The genetic and epigenetic regulation of the program of
preimplantation development, the initiation of placenta
formation (i.e., trophectoderm formation) that is the
critical prerequisite for successful embryo transfer,
implantation, and the establishment of pregnancy; and
3 The initiation and maintenance of normal mammalian embryo
development, as well as the production of healthy oocytes
and eggs that are capable of fertilization and development.
Because of the development of new technology and a
broadening interest, there exists an
opportunity for rapid progress on these critical problems of
mammalian reproductive biology. This progress will depend
upon the use of more efficient in vitro techniques for the
study of mammalian gametes and preimplantation embryos.
This is the case for many gene transfer experiments,
twinning experiments, and a multitude of experiments on the
genetic assessment, morphology, physiology, biochemistry, and
molecular biology of oocytes and eggs and on embryo
development from fertilization through implantation. In
applied science, in vitro procedures are widely
used in commercial endeavors, such as producing twins of
valuable animals and improving the commercial qualities of
livestock for food production. Knowledge gained from the
animal studies may also relate to human in vitro
fertilization, preimplantation development, and embryo
transfer.
Those who use in vitro fertilization, oocyte and
preimplantation development and implantation as model
systems for reproductive toxicology studies also need in
vitro systems that produce high quality oocytes, eggs, and
embryos. Sensitivity of these systems to drugs and
radiation may be much different in culture media that
support growth better than the previously and currently used
media. A far-reaching benefit of this Cooperative Program
will be the improvement of conditions for the production and
genetic assessment of transgenic embryos and animals that
could be used in many biomedical experiments.
Unfortunately, the culture conditions in current use bear
little resemblance to in vivo conditions; our understanding
of nutritional requirements and basic principles of
nutrition is practically nonexistent, and oocytes, eggs, and
embryos raised under these conditions are inferior. This
inferior development may be responsible for defects that
interfere either with fertilization, the implantation
process, or with early post-implantation development
resulting in limited success of embryo transfer experiments.
Despite the fact that numerous successful pregnancies have
followed from in vitro procedures, the efficiency and,
therefore, the cost-effectiveness could be greatly improved
by increased basic knowledge expected from the results of
this Cooperative Program. This would be especially true in
the case of domestic livestock and of non-human primates,
but also for small laboratory animals.
Thus, there are both basic and applied science needs for
improvement of culture conditions for successful in vitro
reproductive procedures for a variety of mammalian species.
It is expected that the results of the Cooperative Program
will provide a better understanding of the general
principles of nutrition, particularly with regard to the
interaction of the preimplantation embryo with the maternal
environment.
The ongoing Cooperative Program with seven research sites
was established by NICHD more than three years ago. During
that time, significant improvements have been made in the
culture conditions for the production of higher quality
mammalian oocytes and eggs that are capable of fertilization
and subsequent development. Significant progress has also
been made in solving the problem of in vitro "blocks" for
preimplantation development for several mammalian species.
It is clear that further improvements in oocyte and embryo
quality will be critical for successful, cost-effective in
vitro fertilization and subsequent development in vitro and
in vivo.
STUDY ORGANIZATION AND RESEARCH SCOPE
Requirements for Applicants:
NICHD invites applications both from current members of the
Cooperative Program (competitive continuation applications),
and from prospective members (new applications). The
minimal requirements for applicants are as follows (See also
Review Criteria and Procedures below):
o Competent, experienced principal investigators who are
committed to this problem;
o Access to properly managed animal colonies with breeding
capabilities;
o Demonstration of the capability of producing and
evaluating sufficient numbers of oocytes, eggs, or embryos
for sound statistical analysis;
o Experience with in vitro fertilization and/or
preimplantation development followed by embryo transfer;
o Excellent technical resources necessary for conduct of
the experiments; and
o Evidence of departmental and institutional support and
commitment.
Direction and Management: The Steering Committee:
Planning and implementation of the study will be done by a
Steering Committee consisting of the Principal Investigators
from each of the participating sites, one NICHD staff member
from the Reproductive Sciences Branch who will serve as
Research Coordinator, and an independent chairperson. To
ensure impartiality, the independent chairperson will be a
scientist of national stature who is not participating as a
Principal Investigator and who is mutually acceptable to the
participants.
General Scope of the Study:
The protocols will be approved, developed and/or modified by
the Steering Committee through a consensus process. The Program
is expected to have the following features:
o Different sites that emphasize the study of different
aspects of the culture environment and utilize different
species; some sites may emphasize micronutrients, some may
emphasize macronutrients, and some will study other aspects
of the environment. This underscores the need for
coordination and communication;
o The determination and prioritization of approaches to be
taken;
o Principles obtained from research on one species can be
rapidly tested in other species;
o Establishment of significant endpoints, including
initiation of pregnancy and birth; methods for evaluation of
endpoints;
o Some sites will place more emphasis on oocyte
development, others on preimplantation development, but the
goals of improved quality of embryos will be a necessary
feature;
o Establishment of detailed experimental design, in order
to maximize chances of success and to facilitate
statistical analysis;
o Transmission of progress reports to the cooperating sites
and NICHD;
o Analysis and dissemination of results; and
o Meeting at least three times each year to discuss
progress and future plans.
In general, the Program will be conducted in the three
phases given in the OVERVIEW section. However, since
extensive evolution of the Program is expected, the Phases
are expected to overlap.
Content of Applications:
A response to this Request for Applications (RFA) should consist
of a proposal that includes:
o A description of the capabilities of the site to meet or
exceed the minimal requirements (see STUDY ORGANIZATION AND
RESEARCH SCOPE above);
o A proposed five-year research plan that should be the
applicant's perception of the study and of his/her
cooperative role. This plan should demonstrate the
applicant's knowledge, ingenuity, practicality, and
commitment to improve the culture conditions for non-human
in vitro oocyte development, fertilization and/or in vitro
preimplantation development followed by embryo transfer.
o All essential information in the body of the proposal
rather than in the Appendix.
o Current members who wish to submit competitive
continuation applications should prepare a renewal proposal,
and are required to list significant progress they have made
in this Program and indicate how they have met any special
cooperative agreement terms and conditions of their awards.
In order to respond to these requirements, current members
may use up to five additional pages in the Progress Report
section of their proposals.
MECHANISM OF SUPPORT
The funding mechanism to be used to assist the scientific
community in undertaking this program of basic and applied
science will be cooperative agreements between participating
sites and NICHD. The major difference between a cooperative
agreement and a research grant is that there will be
substantial programmatic involvement of the NICHD staff
Research Coordinator above and beyond the levels required
for traditional program management of grants. Specifically,
an NICHD staff member will cooperate with the Principal
Investigators as a partner in the research and serve as
Research Coordinator. All parties will agree to accept the
participatory and cooperative nature of the group process.
It is anticipated that up to seven (7) awards will be made with an
award period of five (5) years.
The primary responsibilities of the awardees are:
o Determine experimental approaches
o Design protocols
o Conduct experiments
o Analyze and interpret the results
o Present results and plans to Steering Committee
o Publication of results
o Modify, delete, or add protocols
The degree of programmatic assistance by the NICHD staff
Research Coordinator includes:
o Participation in the development of optimal approaches
and protocol designs (and adjustments of protocols and
approaches when needed). The Research Coordinator will
assist and facilitate the process, rather than directing it;
o Assistance and review of all phases of the study to
assure consistency of protocol compliance, to improve and
strengthen cooperation between the sites, and to help
redirect efforts, if necessary. In the event of
disagreement among participants, NICHD staff will assist in
forming an arbitration panel acceptable to participants (see
below);
o Participation in data analyses, interpretation, and
publication of study results; and
o To determine jointly with awardees, the need to add
additional sites, or to phase out a site when performance
requirements are not met.
The specific terms, conditions, and details of arbitration
procedures pertaining to the scope and nature of the
interaction between NICHD and the participating sites will
be incorporated into the Notice of Grant Award. These
procedures will be in addition to the customary programmatic
and financial negotiations that occur in the administration
of grants. Arbitration procedures will be invoked only when
agreement cannot be reached on programmatic issues that may arise
between
an awardee(s) and the Research Coordinator after the award
has been made. In that event, an arbitration panel will be
formed consisting of one person selected by the Principal
Investigators, one person selected by the Research
Coordinator, and a third person selected by these
two members. The decision of the arbitration panel, by
majority vote, will be binding.
The above Terms of Award are in addition to, and not in lieu
of, otherwise applicable OMB administrative guidelines, HHS
grant administration regulations at 45 CFR Part 74, and
other HHS, PHS, and NIH grant administration policies.
Cooperative agreements are subject to the administrative
requirements outlined in OMB circulars A-102 and A-110; and
all pertinent HHS, PHS, and NIH grant regulations, policies
and procedures, with particular emphasis on HHS regulations
at 42 CFR Part 52 and 45 CFR Part 74, are applicable. The
NIH Information for Management and Planning Analysis and
Coordination (IMPAC) system and indirect cost award
procedures will apply to cooperative agreement awards in the
same manner as for grants. The special arbitration
procedures described above in no way affect the right of a
recipient of a cooperative agreement assistance grant to
appeal an adverse determination in accordance with PHS
regulations at 42 CFR Part 50, Subpart D, and HHS
regulations at 45 CFR Part 16 and 75. Business management
aspects of these awards will be administered by the NICHD
Grants Management Office in accordance with HHS, PHS, and
NIH grant administration requirements.
REVIEW CRITERIA AND PROCEDURES
Review Procedure:
A preliminary review will be done by NICHD staff upon
receipt of the application. Any application that does not
meet the minimal requirements (see STUDY ORGANIZATION AND
RESEARCH SCOPE above) of this RFA will be judged to be
unresponsive to this RFA and will be returned to the
applicant without technical review. Applications that are
complete and responsive may be subjected to a triage
procedure by a peer review group to determine their
scientific merit relative to the other applications received
in response to this RFA. Applications judged to be competitive
for awards will be reviewed in detail in accordance
with established NIH peer review procedures for research
grants. The review will be conducted first for scientific
and technical merit by a special review committee convened
specifically for this purpose by the Scientific Review
Program, NICHD. This will be followed by a second-level
review by the National Advisory Child Health and Human
Development (NACHHD) Council in June 1991.
Criteria for Review:
Applications will be evaluated on scientific and technical
merit according to the criteria listed below. During the
review of applications, ethical and animal welfare issues
will be addressed. If reviewers identify concerns and
problems with respect to animal welfare, this will be
brought to the attention of appropriate NIH officials as
well as the applicant institution.
Evaluation of the proposals will be based upon the
following:
1 Qualifications, Experience, and Commitment of Key
Personnel
o Scientific and administrative abilities of the Principal
Investigator and other team members, as evidenced by
pertinent publications
o Knowledge and experience in areas relevant to the conduct
of the experiments proposed
o Commitment of time for the proposed study and stated
willingness to work and collaborate with other sites
and the NIH in the manner summarized in this RFA
2 Protocols and Procedures
o Responsiveness of the application to the objectives of
the study as outlined in this RFA
o Scientific merit of the proposal
o Demonstration of cost-effectiveness through improved
oocyte and/or embryo quality
3 Facilities and Management
o Adequacy of administrative and technical capabilities
o Adequacy of animal facilities and appropriateness of
animal care management
o Institutional assurance to provide support to the study
in such areas as fiscal administration, personnel
management, space allocation, procurement, planning,
and budgeting
4 Budgeting
o Appropriateness of budget
METHOD OF APPLYING
Application Procedures:
Applications must be submitted on form PHS-398 (Revised
10/88), that is available in most institutional business
offices or from the Division of Research Grants, NIH
(301/496-7441). The conventional presentation format for
regular research grant applications should be used, with
care taken to address the eligibility requirements (see
STUDY ORGANIZATION AND RESEARCH SCOPE) and review criteria
requirements (see REVIEW CRITERIA AND PROCEDURES).
Applications should be identified by checking the
"yes" box in Item Number 2 on the face page of the
application, and typing in the RFA number and the RFA Title.
In addition, the RFA label available in the 10/88 revision
of Application Form PHS 398 must be affixed to the bottom of the
face page. Failure to use this label could result in
delayed processing of your application, such that it may not
reach the review committee in time for review. The original
and four (4) copies should be received by the Division of
Research Grants no later than November 20, 1990.
Applications should be sent or delivered to:
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
5333 Westbard Avenue
Bethesda, Maryland 20892**
In addition to those applications mailed to the Division of
Research Grants, two (2) copies of the application should be
sent or delivered to:
Laurance Johnston, Ph.D.
Scientific Review Program
National Institute of Child Health and Human Development
National Institutes of Health
Executive Plaza North, Suite EPN-520
Rockville, Maryland 20892
Deadline for Submission:
The deadline for receipt of applications by the NIH Division
of Research Grants is November 20, 1990. Late applications
will not be accepted.
Budget:
The format/forms/instructions for budget estimates provided
with research grant application kits (PHS 398) should be
followed. Indirect costs will be awarded in the same manner
as for research grants. Budgets will be reviewed on the
basis of appropriateness for the work proposed. Allowable
costs and policies governing the research grant programs of
the NIH will prevail. The requested budget should not be in
excess of the amount generally requested for a regular
research grant. Include estimates for staffing needs,
although it is expected that some modification will be
needed once the final research protocol(s) has been
developed.
Since the final protocol(s) for this study will not be
exactly known at the time of submission of the application,
the budget request should be based on the plan proposed by
the applicant and should reflect the scope of the project.
The budget should also include estimates of travel expenses
for three meetings of two days each of the Steering
Committee per year. The first meeting will be a Phase I
meeting held in Bethesda, Maryland, in September 1991.
The application should include a detailed summary of all
sources of actual and pending
support for each key investigator participating in the study
with grant or other award number identification and percent
effort committed.
Additional Information:
Timetable
Application Receipt Date: November 20, 1990
Initial Review Date: February/March 1991
Review by NACHHD Council: June 1991
Earliest Award Date: September 1, 1991
It is expected that up to seven (7) applications will be
funded, contingent upon the receipt of meritorious
proposals. For further information, please contact:
Program/Scientific Matters:
Richard J. Tasca, Ph.D.
Reproductive Sciences Branch
Center for Population Research
National Institute of Child Health and Human Development
National Institutes of Health
Executive Plaza North, Room 603
Bethesda, Maryland 20892
Telephone: 301/496-6515
Administrative Policy:
Robin Bissell
Office of Grants and Contracts
National Institute of Child Health and Human Development
National Institutes of Health
Executive Plaza North, Room 505
Bethesda, Maryland 20892
Telephone: 301/496-5001
This program is described in the Catalog of Federal Domestic
Assistance No. 13.864, Population Research. Awards will be
made under the authority of the Public Health Service Act
301 (42 USC 241) and 441 (USC 289d) and administered under
PHS Grant Policies and Federal Regulations 42 CFR Part 52
and 45 CFR Part 74. This program is not subject to A-95 or
Health Systems Agency review.