kristoff@GENBANK.BIO.NET (Dave Kristofferson) (02/01/91)
NOTE: The NIH Guide may be split into more than one mail message to
avoid truncation during e-mail distribution. The first message always
begins with the RFP/RFA summary sections followed by the appended
texts of the full RFP/RFAs.
----------------------------------------------------------------------
OBJECTIVES AND SCOPE
The emphases of this initiative are threefold: (1) to attract new scientific
expertise into the study of the basic mechanisms of kidney and urological
diseases; (2) to encourage interdisciplinary research; and (3) to extend these
basic investigations into innovative clinical and epidemiologic studies of the
causes, therapy, and prevention of kidney and urologic diseases and disorders.
In approaching the study of these disease processes, it is anticipated that
extensive collaboration will be required between individuals in the basic
sciences, including cell biology, molecular biology, immunology, genetics,
epidemiology, biochemistry, physiology, and pathology with clinical sciences.
It is the expressed intent of the announcement to attract into the study of
kidney and urologic disorders new investigators not currently active in this
field and to explore new basic areas that may have clinical research
application. Individual institutions with both basic and clinical research
capabilities are eligible to apply. Inter-institutional collaborative
research arrangements are also appropriate and are encouraged.
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 17
SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDIES
For projects involving clinical research, NIH requires applicants to give
special attention to the inclusion of women and minorities in study
populations. If women or minorities are not included in the study populations
for clinical studies, a specific justification for this exclusion must be
provided. Applications without such documentation will not be accepted for
review.
MECHANISM OF SUPPORT
NIDDK expects to award up to six center grants (P50) in fiscal year 1992 on a
competitive basis. The receipt of up to six competitive continuation
applications from those centers who are current awardees is anticipated.
These applications will compete for awards along with other applications
received in response to this announcement. Foreign institutions are not
eligible to apply. The anticipated awards are for five years and are
contingent upon the availability of appropriated funds. The total amount of
available funds to support this program (including both direct and indirect
costs) is anticipated to be no more than $4.2 million per year. No applicant
may request more than $750,000 in total costs (both direct and indirect costs)
in the initial budget period.
The complete Request for Applications (RFA) and consultation may be obtained
from:
Dr. Ralph L. Bain
Kidney and Urology Research Centers Program Director
DKUHD/NIDDK
Federal Building, Room 102
9000 Rockville Pike
Bethesda, MD 20892
Telephone: (301) 496-8218
REVIEW PROCEDURES
Applications for an award of a research center grant will be evaluated in a
national competition by the NIH peer review process. Applications will be
reviewed initially by a special review committee convened by the NIDDK and
subsequently by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.
METHOD OF APPLYING
Potential applicants are urged to submit a letter of intent to the Program
Director by March 15, 1991, regarding their application. The letter of intent
is nonbinding and is not a precondition for an award. The letter of intent
should include the name(s) of the Principal Investigator(s), principal
collaborators, a descriptive title of the proposed research center, and the
organization(s) involved. Applications must be submitted using PHS Form 398
(Rev. 10/88). The RFA label contained in the application kit must be affixed
to the bottom of the face page of the original copy of the application.
Failure to use this label could result in delayed processing and review of the
application. Complete line 2 of the application face page by inserting the
title and number of this RFA and checking the YES box.
Mail the completed application (original and four copies) to:
Application Receipt Office
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
Simultaneously submit two copies to:
Review Branch, NIDDK
5333 Westbard Avenue
Westwood Building, Room 406
Bethesda, MD 20892
The special single receipt date for submissions in response to this
announcement is July 16, 1991, with earliest funding August 1, 1992.
This program is described in the Catalog of Federal Domestic Assistance No.
93.849, Kidney, Urologic, and Hematologic Diseases Research. Awards will be
made under the authority of the Public Health Service Act, Title III, Section
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 18
301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS
grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.
SCIENCE EDUCATION PARTNERSHIP AWARD
RFA AVAILABLE: ADAMHA AD-91-01
NIH OD-91-01
P.T. 44; K.W. 0720000, 0710000
Alcohol, Drug Abuse, and Mental Health Administration
National Institutes of Health
Letter of Intent Receipt Date: March 15, 1991
Application Receipt Date: April 25, 1991
BACKGROUND INFORMATION
The President and the Nation's Governors have declared six "National Education
Goals," one of which is that by the year 2000, students in the United States
will be the world leaders in science and mathematics achievement. Further,
unless there are adequate numbers of students entering and remaining in the
mathematics and scientific fields of education, the United States will not
have a sufficient supply of scientists, engineers, and technicians to meet the
Nation's future workforce needs. There is also the need for a scientifically
literate society that understands the role of science, biology, and
technology. There is a lack of public understanding of behaviors that
increase the risk for disease, the use of animals in behavioral and biomedical
research, and the necessity for basic research to make progress toward
improving health. To help address these issues, the Alcohol, Drug Abuse, and
Mental Health Administration (ADAMHA) and the National Institutes of Health
(NIH) are initiating in Fiscal Year 1991 the Science Education Partnership
Award (SEPA) Program. To meet their respective missions, the ADAMHA and the
NIH are issuing this joint Request for Applications (RFA) for SEPA proposals.
Applicants may submit multiple different applications under this RFA; however,
substantially similar proposals may not be submitted to the two agencies.
PROGRAM DESCRIPTION
The SEPA Program will support grants designed to encourage scientists to work
with educators and community organizations to improve student and public
understanding of science, and increase interest of young people in scientific
careers. The focus of student activities is to be at the kindergarten through
twelfth grade (K-12) level. The scientists who study disease and illness and
those who carry out basic research relating to these disorders, have a major
contribution to make by conveying their knowledge and also the excitement in
doing research. However, it is also essential that scientists work with
educators, school administrators, community leaders, the media, and others in
order to make effective contributions to improving science education and
improving public understanding of both the process and accomplishments of
science.
ADAMHA will support partnership projects that focus on any scientific area
relevant to the ADAMHA mission. Hence, the focus of this award is on building
partnership programs. ADAMHA is especially interested in projects that focus
on scientific knowledge about the brain and behavior and their relation to the
addictive and mental disorders. This includes the basic sciences underlying
these disorders, such as the neurosciences, psychology, pharmacology,
genetics, and other relevant sciences.
The NIH SEPA Program will support the development of model programs that join
working scientists and educators in enhancing the precollege science education
and public understanding in such biomedical science areas as molecular
biology, molecular genetics, immunology, neuroscience, and bioinformatics, as
well as ethical issues, the benefits and risks of genetic engineering, and the
role of environmental health.
ADAMHA and NIH will consider cofunding of projects focussing on general
aspects of health science (e.g., the responsible use of animals in biomedical
and behavioral science or biotechnology) or scientific areas that cut across
the mission of both agencies (e.g., neurosciences, genetics, and health and
behavior). A single application should be submitted for such projects.
The ADAMHA and the NIH encourage and support the initiation of cooperative
efforts among diverse elements in the scientific and education community,
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 19
including university scientists, elementary and secondary schools,
foundations, private industry, the media, and museums, to develop model
programs for increasing scientific literacy. The ADAMHA/NIH SEPA Program
seeks to focus on the improvement of science education through partnerships
between public and private sector organizations and the working scientists.
Carefully crafted partnerships can create channels for transferring
information about new scientific discoveries, improve curricula, and develop
textbooks and other materials that increase and impart to students, teachers,
and the general public the utility of biomedical/behavioral research. The
essential feature of the program is the active participation of scientists
with the scientific and technical knowledge and resources with the knowledge
and pedagogical expertise of educators. Research institutions are encouraged
to provide, from non-Federal sources, incentives for their scientists to
participate in the SEPA Program. These incentives may include the awarding of
sabbaticals, time released from other duties, or special institutional
recognition to individuals, to permit them to participate in the program.
Such applicants are also encouraged to use institutional funds released as a
result of the SEPA award (e.g., investigators' salaries) for purposes
consistent with this award.
ADAMHA and NIH seek the development of model projects and, therefore, priority
will be given to applications with the potential for widespread use and
replication.
MECHANISM OF SUPPORT/AVAILABILITY OF FUNDS
This RFA will use the grant-in-aid for education projects (R25).
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. Except as otherwise stated in
this RFA, awards will be administered under PHS grants policy as stated in the
Public Health Service Grants Policy Statement.
This RFA is a one-time solicitation. The ADAMHA and the NIH expect that $2
million will be available to each agency (a total of $4 million) during FY
1991 to support this initiative. Subject to the availability of funds and
receipt of a sufficient number of meritorious applications, it is anticipated
that approximately ten to twenty projects will be supported.
Applicants may request support for up to three years. Annual direct cost
requests for the proposed activities are expected to range from approximately
$100,000 to $250,000. Indirect costs will be provided. The anticipated award
date is September 30, 1991.
REVIEW PROCEDURES
Applications that are complete and responsive will be evaluated for
educational and scientific/technical merit by an appropriate peer review group
convened by ADAMHA and NIH. Applications may be subjected to triage by a peer
review group to determine their educational and scientific merit relative to
other applications received in response to this RFA. Those applications
judged to be competitive will undergo further merit review. The second level
of review will be provided by the National Advisory Mental Health Council
and/or the National Advisory Research Resources Council.
METHOD OF APPLYING AND LETTER OF INTENT
The Application for Public Health Service Grant Form PHS-398 (revised 10/88)
must be used in applying for these grants. These forms are available at most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, NIH, 5333 Westbard Avenue, Bethesda, Maryland
20892, (301) 496-7441. Prospective applicants must request a copy of the
complete RFA, which includes supplemental instructions for completion of the
Form PHS-398, from the staff identified below (see INQUIRIES).
Prospective applicants are asked to submit, by March 15, 1991, a letter of
intent that includes a descriptive title of the proposed project; the name,
address, and telephone number of the Principal Investigator; the names of
other key personnel, the participating institutions; and the number and title
of the RFA in response to which the application is being submitted.
Although a letter of intent is not required, is not binding, and does not
enter into the review of subsequent applications, the information that it
contains is extremely helpful in planning for the review of applications. It
allows staff to estimate the potential review workload and to avoid possible
conflict of interest in the review.
The ADAMHA letter of intent should be sent to the Deputy Director, Division of
Extramural Activities, National Institute of Mental Health, Parklawn Building
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 20
Room 9-105, 5600 Fishers Avenue, Rockville, MD 20857. The NIH letter of
intent should be sent to Dr. Marjorie A. Tingle (see address below). A copy
of the letter of intent should be addressed to:
Anthony Demsey, Ph.D.
Associate Director for Referral and Review
Division of Research Grants
National Institutes of Health
Westwood Building, Room 338
5333 Westbard Avenue
Bethesda, MD 20892**
INQUIRIES
Written or telephone inquiries regarding this RFA, and requests for the
complete RFA may be directed to either:
Dr. Joel W. Goldstein
ADAMHA SEPA Program
Room 13-103
5600 Fishers Lane
Rockville, MD 20857
Telephone: (301) 443-9674
or
Marjorie A. Tingle, Ph.D.
NIH SEPA Program
National Center for Research Resources
Westwood Building, Room 10A11
5333 Westbard Avenue
Bethesda, MD 20892**
Telephone: (301) 496-6743
ADAMHA awards are under the authority of Section 301 of the Public Health
Service Act, as amended, (42 U.S.C. 241). NIH awards are under authorization
of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285). All awards will be
administered under PHS grant policies and Federal Regulations 42 CFR 52 and 45
CFR Parts 74 and 92. This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.
MULTICENTER COOPERATIVE AGREEMENT FOR STUDYING NEURAL TUBE DEFECTS IN MUTANT
MICE
RFA AVAILABLE: HD-91-01
P.T. 34; K.W. 0710030, 1002004, 1002019, 1002059, 0755030
National Institute of Child Health and Human Development
Application Receipt Date: April 22, 1991
OVERVIEW
Neural tube defects (NTDs) are among the most common congenital defects,
occurring at a rate of 1-2/1000 live births. Despite their frequency the
causes of NTDs are still not understood. The National Institute of Child
Health and Human Development (NICHD) invites research applications from
investigators willing to participate with NICHD assistance under cooperative
agreements in a multicenter cooperative program designed to investigate the
etiology of neural tube defects. The objective of the study is to bring
together a multidisciplinary group of investigators to characterize mammalian
neurulation in a mouse genetic model for spina bifida, the curly tail mouse,
developed under NICHD contract. Particular emphasis will be given to
individual studies examining the molecular, cellular, biophysical, and
morphological mechanisms involved in neural tube formation. The cooperative
agreement mechanism has been chosen to facilitate identification of the
etiology of spina bifida by coordinating research among the individual sites
within the program. Analyses of the various aspects of NTD formation will be
coordinated among the investigators, and it is anticipated that there will be
substantial evolution of the program as new findings are obtained and shared.
The benefit of such a cooperative venture will be to better define the
mechanisms by which normal neurulation occurs and to characterize the
processes leading to NTDs in a well defined mammalian model with an
applicability to the human condition.
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 21
MECHANISM OF SUPPORT
Support will be available through the cooperative agreement mechanism (U01)
between individual investigators and the NICHD. The major difference between
a cooperative agreement and a research grant is that there will be substantial
programmatic involvement of NICHD staff above and beyond the levels required
for traditional program management of grants.
It is anticipated that four awards totaling $800,000 (direct costs) for the
first year will be made with an award period of five years.
REVIEW PROCEDURES
Applications will be reviewed by the NICHD staff for responsiveness to the
Request for Applications (RFA) and may receive a triage review for relative
scientific merit by a peer review group. Scientific and technical merit will
be evaluated by a special review committee convened specifically for this
purpose by the Division of Scientific Review, NICHD. A second-level review
will be done by the National Advisory Child Health and Human Development
Council.
APPLICATION PROCEDURE
Applications must be submitted on form PHS 398, Revised 10/88.
ADDITIONAL INFORMATION
Potential applicants are encouraged to request the detailed RFA by
telephoning:
Delbert Dayton, M.D.
Genetics and Teratology Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
Executive Plaza North, Room 643
9000 Rockville Pike
Bethesda, MD 20892
Telephone: (301) 496-5541
The full RFA is also available on the electronic version of the NIH Guide for
Grants and Contracts, the E-Guide.
ERRATUM
ADDENDUM: NATIONAL INSTITUTE ON DRUG ABUSE - ANNOUNCEMENT AND GUIDELINES -
AUGUST 1990
PA: PA-90-31
P.T. 34; K.W. 0404009, 1014006
National Institute on Drug Abuse
As an addendum to the National Institute on Drug Abuse (NIDA) Research Grants
Program Announcement and Guidelines, PA-90-31 (published in the NIH Guide for
Grants and Contracts, Vol. 19, No. 32, September 7, 1990, NIDA wishes to
include as part of Research Support Mechanisms the following: (7) Program
Project Grants (P01). Although the P01 mechanism was included in the
September 7, 1990, NIH Guide notice, the complete, printed copy of the
announcement inadvertently omitted it as one of the possible support mechanism
acceptable under this announcement. Today's notice is to confirm that the P01
support mechanism is acceptable under announcement PA-90-31. All other
aspects of the announcement remain unchanged.
**THE MAILING ADDRESS GIVEN FOR SENDING APPLICATIONS TO THE DIVISION OF
RESEARCH GRANTS OR CONTACTING PROGRAM STAFF IN THE WESTWOOD BUILDING IS THE
CENTRAL MAILING ADDRESS FOR THE NATIONAL INSTITUTES OF HEALTH. APPLICANTS WHO
USE EXPRESS MAIL OR A COURIER SERVICE ARE ADVISED TO FOLLOW THE CARRIER'S
REQUIREMENTS FOR SHOWING A STREET ADDRESS. THE ADDRESS FOR THE WESTWOOD
BUILDING IS:
5333 Westbard Avenue
Bethesda, Maryland 20816
NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - Page 22
------------------------- Full text of RFAs -------------------------
REQUEST FOR APPLICATIONS
DEVELOPMENT OF MODELS FOR PEDIATRIC AIDS
RFA AVAILABLE: AI-91-04
P.T. 34; K.W. 0715008, 0755020, 0770005
National Institute of Allergy and Infectious Diseases
Letter of Intent Receipt Date: March 11, 1991
Application Receipt Date: April 22, 1991
The National Institute of Allergy and Infectious Diseases
(NIAID) invites applications for individual research project
(RO1) grants to conduct basic research in the development of
animal models and in vitro models for pediatric
human immunodeficiency virus (HIV)
infection and disease. HIV is now recognized as the
causative agent of the Acquired Immunodeficiency Syndrome
(AIDS). However, the disease that occurs in the pediatric
population is different from the disease that occurs in
adults. Disease in very young children progresses more
rapidly than in adults and the range of opportunistic
infections (OIs) differs with more bacterial infections
occurring in children. Further, the immunosuppressive
effects of HIV are superimposed on immature
immune and nervous systems in children. Thus, the pathogenesis of
lentivirus infections and the associated opportunistic
infections are likely to be different from adults in developing animals.
Animal models of fetal or neonatal
infection with lentiviruses related to HIV and in vitro
models of placental infection are needed to study these
aspects of disease and facilitate the identification and
evaluation of therapies with greatest potential for treating
these special populations.
Research efforts considered responsive to this RFA include
delineation of the events leading to the establishment of
primary infection in fetal or neonatal animals, the
mechanisms of virus spread, viral or placental factors
modulating infection, and the outcomes of infection during
development, including immune suppression and opportunistic
infections. Investigators should plan to apply the models
described above to the design of new anti-HIV therapies to
prevent or interrupt the transmission of HIV from mother to
offspring. The models should also be applicable for testing
the efficacy of such therapies.
I. BACKGROUND
NIAID is playing a central role in the investigation of
AIDS. Research
efforts directed toward the pathogenesis, prevention, and
treatment of the disease and its sequelae have intensified.
The NIAID has undertaken a lead role in organizing
scientists into National Cooperative Drug Discovery Groups
for the Treatment of HIV Infection (NCDDG-HIV) and of the
opportunistic infections associated with AIDS (NCDDG-OI).
In vitro screening of potential therapies and the more
targeted approach of the NCDDG's have proven extremely
valuable and have led to identification of several new
therapies currently undergoing preclinical development as
well as several therapies in clinical trials. The NIAID
also supports individual investigators in their research
efforts toward the discovery and development of therapies
for AIDS. The NIAID supports and oversees the AIDS Clinical
Trials Groups (ACTG), the premier NIH-funded U.S. clinical
trials effort for the evaluation of agents directed against
HIV and against the
IOs and malignancies that are sequelae
of HIV infection.
To date most preclinical drug development efforts have
concentrated on generating data to support clinical trials
in HIV-infected adults. Studies focused on the unique
aspects of infection of the fetus and of the neonate need to
be expanded so that information can be gained concerning the
unique targets for therapies that might be present in this
population. Children born to HIV-positive women are one of
the fastest growing populations of AIDS patients.
Therefore, the NIAID now wishes to expand the scope of
research currently being conducted in this area.
The rational design and optimization of therapies for
preventing transmission or treating the neonate and
pediatric populations require a thorough understanding of
the disease process in the fetus and in developing animals.
If more effective therapies are to be found for pediatric
HIV disease, the disease and mechanisms of infection must be
more clearly defined. Aggressive research is necessary to
develop models in which questions of pathogenesis and
mechanism of infection may be answered. Elucidation of the
mechanisms of transplacental infection of the fetus (via
free virus or infected cells) and the effects of infection
on the developing immune system and nervous system is
critical. This research needs to include investigation of
the regulation of virus expression in fetal or placental
tissues and definition of viral and/or cellular factors that
may effect transplacental infection. Such research in
appropriate models will facilitate the identification and
exploitation of methods to prevent HIV transmission and/or
prevent the spread of infection in the fetus, neonate or
pediatric patients.
II. OBJECTIVES AND SCOPE
NIAID wishes to stimulate research to develop animal models
and in vitro models to study the origin, consequences, and
treatment of pediatric infection with HIV, lentiviruses, or
relevant retroviruses closely related to HIV. The models
should be used to examine the pathogenesis of infection in
the fetus or neonate, to examine effects of infection on
developing rather than adult organisms, to investigate
infection of the placenta and mechanisms of transplacental
infection, and to define viral and placental factors that
affect transplacental infection.
Specifically, research efforts considered responsive to this
Request for Applications (RFA) are to develop and use: (i) an in
vitro model of infection of placenta with HIV suitable for
examining the regulation and pathogenesis of HIV and for
identifying unique targets for new therapies; and/or (ii) an
animal model of transmission of virus, studying transplacental
transport of virus or infected cells, the mechanisms of
infection, and targets for therapies; or (iii) an animal model of
lentivirus infection of fetal or neonatal animals for studying
the pathogenesis of the virus, development of disease, and the
action of therapies designed to prevent transmission; and/or (iv)
an animal model, using a lentivirus or relevant retrovirus, to
define the viral and/or cellular factors that effect
transplacental infection and that represent potential targets for
new therapies. Investigators should plan to apply the models
described above to the design and preclinical evaluation of
anti-HIV therapies to prevent or interrupt the transmission of
HIV from mother to offspring. In addition, use of HIV or a
lentivirus such as SIV is preferred. Use of other retroviruses
may be considered responsive IF there is evidence presented that
it models HIV disease closely. Applications that involve
collaborating scientists or institutions are encouraged, but not
required, for response to this announcement.
Research plans to: (i) solely evaluate various compounds for
their ability to cross the placenta in an animal model, (ii)
evaluate vaccine-related therapies or immune responses,
(iii) develop or use models that employ murine leukemia
retroviruses, or (iv) develop or use transgenic models or
models in which virus is injected directly into fetuses as a
model of transmission are not considered responsive to this
announcement.
Recent reports have documented HIV infection of cells within
the human placenta. However, little is known about
regulation of HIV expression, viral replication, or
mechanisms of infection in the placenta. For example,
Hofbauer cells, macrophage-like cells present within the
placenta, may act as a reservoir for infection of both
maternal and fetal cells. Factors that regulate HIV
expression in the placenta should also be investigated to
determine whether there are unique potential therapeutic
targets in the placenta. Similarly, there may be viral and/or
cellular factors that modulate HIV expression, infectivity,
or transmission within the placenta. Studies directed
toward these and other questions related to infection of
human placenta by HIV are greatly needed.
Although it is assumed that HIV infection of the fetus
occurs by some type of transplacental transmission of the
virus, virtually nothing is known about the actual
mechanism(s) of virus transport. Questions remain about
whether virus is transmitted as free virus or by infected
cells and little information is available on virus uptake or
release from cells within the placenta. Once the routes of
transport of virus are determined, the rational selection or
design of therapies to interrupt transmission will be
greatly facilitated. For example, if transmission occurs
via infected cells, therapies to reduce free virus are not
likely to be effective. While certain information may be
obtained from studies using HIV and human placental cells in
vitro, other models using pregnant animals, and other
lentiviruses may contribute valuable information on
transmission in vivo.
Prenatal or perinatal infection with several pathogens is known
to occur in humans. For CMV, HSV, rubella, and toxoplasma,
disease and consequences of infection in the infant are different
from consequences in adults. This difference in disease course
and severity may reflect the immature immune system of the infant
at the time of infection. Targets for HIV infection include the
immune system and the nervous system, both of which are still
developing after birth in humans and most primates. The
pathogenesis of HIV may differ in the fetus or neonate compared
to adults due to the immaturity of the target organs and, in
particular, the immaturity of the immune system. Indeed, OIs
differ in infants and adults infected with HIV. There may also
be broader differences in the response of the developing organism
to infection. For example, failure to thrive or delayed growth
are associated with HIV infection of very young children but have
no real correlate in adult patients.
These differences point to a critical need to develop new
animal models using a lentivirus or relevant retrovirus
infection that accurately reflect the characteristics of
disease unique to developing animals. Animal models are
also needed to evaluate the role of the developing immune
system in the pathogenesis of HIV infection and the impact
of infection on specific developmental patterns, including
the effects of infection on development of the immune and
nervous systems. Results from this research on the origin
and consequences of lentivirus infection of the placenta and
developing animals should be applied to the identification
and evaluation of methods to prevent HIV transmission,
spread, and its sequelae.
III. MECHANISM OF SUPPORT
This RFA will use the R01 grant mechanism. The NIAID has
allocated $1,000,000 (total costs) for the initial year of
funding applications received in response to this RFA. It
is anticipated that three to five applications will be
funded. The award of grants pursuant to this RFA is
contingent upon the continuing availability of funds for
this purpose and upon receipt of a sufficient number of
applications of high scientific merit.
This RFA is a one-time solicitation. Generally, future
unsolicited competing continuation applications will compete with
all investigator-initiated applications and be reviewed by a
Division of Research Grants study section. However, should the
NIAID determine that there is a sufficient continuing program
need, the NIAID may announce a request for renewal applications.
IV. MINIMUM REQUIREMENTS FOR APPLICATION
Any domestic or foreign institution, university, medical
college, hospital, or laboratory or other public, private,
or for-profit institution is eligible. Applicants may
request up to four years of support.
V. LETTER OF INTENT
Prospective applicants are asked to submit by March 11, 1991, a
letter of intent that includes a descriptive title and a
description (not to exceed one page) of the proposed research.
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 is not
binding, nor is it a requirement for submission of an
application. The letter of intent should be sent to:
Polly R. Sager, Ph.D.
Senior Scientist
Developmental Therapeutics Branch
Division of AIDS, NIAID
6003 Executive Blvd., Room 244P
Bethesda, MD 20892
FAX Number: (301) 480-5703
VI. CONSEQUENCES OF LACK OF RESPONSIVENESS TO THE RFA
Applications that are incomplete for review or nonresponsive
to this RFA will be screened out by NIH staff upon receipt
and returned to the applicants without further
consideration.
VII. REVIEW METHOD AND PEER REVIEW CRITERIA
Those applications that are complete and responsive may be
subjected to a triage by a peer review group to determine
their scientific merit relative to the other applications
received in response to this RFA. The NIH will withdraw
from competition those applications judged by triage to be
noncompetitive and notify the applicant and institutional
business official.
Those applications judged to be competitive will be further
reviewed for scientific and technical merit by a Review
Committee convened by the Division of Research Grants, NIH.
The second level of review will be provided by the National
Advisory Allergy and Infectious Disease Council.
Awards will be based on scientific and technical merit,
significance, originality, adequacy of research experience,
commitment, and time availability of the Principal
Investigator and other key personnel, adequacy of
facilities, and reasonable cost.
VIII. METHOD OF APPLYING
A. Receipt Date
The deadline for receipt of applications is April 22, 1991.
Applications received after this date will be considered not
responsive to this RFA and will be returned without review.
B. General
1. The research grant application form PHS-398
(rev. 10/88) must be used in applying. These forms are
available at most institutional business offices and from the
Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449,
9000 Rockville Pike, Bethesda, Maryland 20892.
Submit a signed, typewritten original of the application,
including the Checklist, and 23 signed, exact, single-sided
photocopies, in one package to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
2. TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH
THIS RFA:
a. The application form should have "DEVELOPMENT OF
MODELS FOR PEDIATRIC AIDS" (RFA AI-91-04) typed on
line 2 of the face page of the application form.
b. The RFA label provided with the instructions must
be affixed to the bottom of the face page. Failure to
use this label could result in delayed processing of
your application so that it may not reach the review
committee in time for review.
IX. INQUIRIES
Additional information may be obtained from:
Polly R. Sager, Ph.D.
Developmental Therapeutics Branch
Division of AIDS, NIAID
6003 Executive Blvd., Room 244P
Bethesda, MD 20892
Telephone: (301) 496-0636
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and Transplantation
Research. Grants are awarded under the authority of the
Public Health Service Act, Title IV, Section 301, as
amended, Public Law 78-410, Public Law 97-219, Public Law
99-158, Public Law 99-500, and Report 99-711 to accompany HR
5233 and administered under PHS grant policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74. This program is
not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.
REQUEST FOR APPLICATIONS
DEVELOPMENT OF MODELS FOR PLACENTAL
AND PEDIATRIC METABOLISM, TOXICITY, AND TRANSPORT OF anti-HIV
DRUGS
RFA: AI-91-05
P.T. 34; K.W. 0785170, 0715008, 0740012, 1007009, 0755025
National Institute of Allergy and Infectious Diseases
Letter of Intent Receipt Date: March 11, 1991
Application Receipt Date: April 22, 1991
The National Institute of Allergy and Infectious Diseases
(NIAID) invites applications for individual research project
(RO1) grants to conduct basic research in the development of
animal models and in vitro models to assess the metabolism,
transport, and toxicity of anti-HIV drugs in the placenta, the
fetus and the neonate. HIV is now recognized as the causative
agent of the Acquired Immunodeficiency Syndrome (AIDS). Children
born to HIV-positive mothers and HIV-infected women are now the
fastest growing populations of AIDS patients. Traditionally,
new therapies were available to children and pregnant women only
after extensive clinical experience in other adult populations.
However, because of the magnitude and severity of the AIDS
epidemic, therapies are now being tested in children and
pregnant women early in clinical development. Frequently, there
is minimal information available from preclinical studies to
provide a scientific basis for the use of therapeutics in these
specific patient populations.
Some of the therapeutic agents now in use or being considered
for use in clinical trials of pregnant women and their children
include: azidothymidine (AZT), dideoxyinosine (ddI), other
nucleoside analogs, soluble CD4-conjugates, protease inhibitors,
and immunoglobulins. Animal models and in vitro models are
needed to assess the metabolism and transport of AIDS therapies
in the placenta and in the fetus and neonate. In addition, the
mechanisms of toxicity of therapeutics to the placenta, fetus,
and neonate must be examined. This preclinical information will
facilitate optimizing the efficacy and minimizing the toxicity
of drugs evaluated in these patient populations.
NIAID now wishes to stimulate research to develop animal models
and in vitro models to assess the metabolism, transport, and
toxicity of anti-HIV drugs in the placenta, fetus, and
neonate. Applications that involve collaborating scientists or
institutions are encouraged but not required for response to
this announcement. Research plans to evaluate standard
teratology, reproductive toxicology, or pharmacokinetics in
rodents are not considered responsive to this announcement.
I. BACKGROUND
NIAID is playing a central role in the investigation of
AIDS. Research efforts directed
toward the pathogenesis, prevention, and treatment of the disease
and its sequelae have intensified. The NIAID has undertaken a
lead role in organizing scientists into National Cooperative
Drug Discovery Groups for the Treatment of HIV infection (NCDDG-
HIV) and of the opportunistic infections associated with AIDS
(NCDDG-OI). In vitro screening of potential therapies and the
more targeted approach of the NCDDG's have proven extremely
valuable and have led to identification of several new therapies
currently undergoing preclinical development as well as several
therapies in clinical trials. The NIAID also supports
individual investigators in their research efforts toward the
discovery and development of therapies for AIDS. The NIAID
oversees and supports the AIDS Clinical Trials Groups who
conduct clinical trials to evaluate therapies for HIV
infections and the opportunistic infections associated with
AIDS.
To date, most preclinical drug development efforts have
concentrated on generating data in support of clinical trials in
HIV-infected adults. Preclinical studies to investigate the
unique aspects of treating pregnant women who are HIV-positive
or their children need to be expanded. Treatment of infants is
complicated by the fact that approximately 30% of children born
to HIV-positive mothers are infected with HIV, while about 70%
are uninfected. Currently, there are no methods readily
available to determine before or soon after birth which children
are actually infected. Thus, consequences of exposure to
therapies in uninfected children must be considered. The NIAID
wishes to expand the scope of research currently being conducted
to examine pharmacology, pharmacokinetics, and toxicity issues
that are specific to optimizing the use of AIDS therapies in
pregnant women and children.
The optimal design of clinical trials of AIDS therapies in HIV-
positive pregnant women and their infants requires a basic
understanding of the pharmacology, pharmacokinetics, and
mechanisms of toxicity of AIDS therapeutic agents in these
populations. There is a paucity of information related to
mechanisms of drug handling and toxicity of therapeutics used to
treat HIV-infected pregnant women and their children.
Aggressive research is necessary to develop models in which
questions of mechanism of transplacental transfer, placental and
fetal metabolism, and placental and developmental toxicity of
AIDS therapies may be answered. Specifically, models are needed
to: (i) define mechanisms of transport of therapies across the
placenta; (ii) investigate metabolism of therapies in the
placenta, fetus, and neonate; (iii) define the
distribution and pharmacokinetics parameters of drugs
administered to pregnant and neonatal animals; (iv) elucidate
the mechanisms of toxicity related to AIDS therapies in the
placenta, fetus, and neonate.
II. OBJECTIVES AND SCOPE
NIAID wishes to stimulate research to develop animal models and
in vitro models to assess the metabolism, transport, and
toxicity of anti-HIV drugs in the placenta and in the fetus and
neonate.
Specifically, research efforts considered responsive to this RFA
are to develop and use: (i) in vitro models to assess the
metabolism, transport, and mechanisms of toxicity of anti-AIDS
therapies in the placenta; (ii) animal models to assess the
transplacental transport of AIDS therapies and to determine
pharmacokinetics parameters to serve as the basis for clinical
trials in humans; (iii) animal models to assess the metabolism
and distribution of AIDS therapies in the fetus and neonatal
animals to serve as the basis for clinical trials in humans;
(iv) animal models to assess mechanisms of toxicity relevant to
use of drugs in pregnant women and very young infants. The
emphasis should be on issues of pharmacology and toxicity that
are specific to the use of AIDS therapies in pregnant women and
children born to HIV-positive women. The Developmental
Therapeutics Branch of the Division of AIDS will assist in
providing therapeutic agents to be studied and, where possible,
analytical methods for detection of drug.
It has been presumed that in order for a therapy to be most
effective in preventing prenatal/perinatal transmission of HIV,
the therapy must cross the placenta. Because the exact timing of
infection of the fetus with HIV is not known, drugs have been
sought that exert anti-viral activity in maternal tissues and in
the fetus; this requires transport of the therapeutic from
maternal to fetal circulation. However, little is known about
the mechanisms of transplacental transport for most AIDS
therapies now in the clinic or proposed for use in pregnant
women. Therefore, models are needed to define the transport of
drugs either in vitro, using human placentae, or in animals such
as non-human primates having placental structure and function
similar to humans. The information gained from these models
should be applicable to the design of clinical trials in
pregnant women.
Similar models to those developed for the transport studies
described above are needed to define the pharmacokinetics
parameters for therapies to be used in HIV-positive pregnant
women and neonates. For example, information on drug clearance
in pregnant versus non-pregnant animals, on the plasma half-time
of drugs in maternal and fetal circulation, on accumulation of
drug in the amniotic fluid, and pharmacokinetics in the neonate
would contribute greatly to the preclinical development of new
therapies and the design of clinical protocols.
The capacity to metabolize drugs varies with tissue and organ
type and with age. The placenta itself contains a variety of
enzymes, including p450s that metabolize drugs. The human fetus
has very limited capacity to metabolize drugs, but metabolic
enzymes increase during late gestation and in the early
postnatal period. These metabolic parameters may affect the
distribution and pharmacokinetics of administered drugs. Thus,
there is a need to investigate, using human placenta in vitro
and animal models, the metabolism of AIDS therapies within the
placenta, in the fetus, and in the neonate. The information
from these studies should assist in the interpretation of data
on transport and pharmacokinetics of therapeutic agents.
Treatment of HIV-infected pregnant women and their potentially
uninfected infants in utero requires that the consequences of
exposure to therapy be considered. Toxicity related to
treatment may occur directly, affecting the function of the
placenta. For example, drugs that demonstrate placental
toxicity may act on the microvasculature of the placenta. Other
mechanisms of direct toxicity are related to regulation of
hormones necessary to maintain placental function. Questions of
direct placental toxicity may be examined using human placenta
in vitro or using animal models with placental function similar
to humans.
Drugs may also have toxic effects on the fetus exposed to drug
in utero, or on the neonate directly receiving drug. These
effects may range from frank terata to subtle effects on
developmental progress observed only much later. In addition,
toxic effects, as defined in adult animals or humans, may differ
in organisms still undergoing development. For example,
neurotoxicity that may be clearly defined in adults may appear
as a more diffuse, generalized syndrome if exposure occurred
during development. While standard protocols exist and are
routinely used for assessing the teratogenic potential of drugs,
the more delayed effects are not well studied or understood.
Thus, models in which to investigate the effects of therapy on
the developing organism are needed; special attention needs to
be paid to effects on development of the immune system and
immune function and on the nervous system, examining development
of motor, sensory, and cognitive function. Information from
these model systems would be invaluable in the design of
clinical trials using therapies during pregnancy and during
early infancy.
Research plans to evaluate standard teratology, reproductive
toxicology, or pharmacokinetics in rodents are not considered
responsive to this announcement.
III. MECHANISM OF SUPPORT
This Request for Applications (RFA) will use the R01 grant mechanism. The
NIAID has
allocated $1,000,000 (total costs) for the initial year of
funding applications received in response to this RFA. It is
anticipated that three to five applications will be funded. The
award of grants pursuant to this RFA is contingent upon the
continuing availability of funds for this purpose and upon
receipt of a sufficient number of applications of high
scientific merit.
This RFA is a one-time solicitation. Generally, future
unsolicited competing continuation applications will compete
with all investigator-initiated applications and be reviewed by
a DRG study section. However, should the NIAID determine that
there is a sufficient continuing program need, the NIAID may
announce a request for renewal applications.
IV. MINIMUM REQUIREMENTS FOR APPLICATION
Any domestic or foreign institution, university, medical
college, hospital, and laboratory or other public, private or
for-profit institution is eligible. Applicants may request up
to four years of support.
V. LETTER OF INTENT
Prospective applicants are asked to submit, by March 11, 1991, a
letter of intent that includes a descriptive title and a
description (not to exceed one page) of the proposed research.
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. The letter of intent should be
sent to:
Polly R. Sager, Ph.D.
Senior Scientist
Developmental Therapeutics Branch
Division of AIDS, NIAID
6003 Executive Blvd., Room 244P
Bethesda, MD 20892
FAX number: (301) 480-5703
VI. CONSEQUENCES OF LACK OF RESPONSIVENESS TO THE RFA
Applications that are incomplete for review or nonresponsive to
this RFA will be screened out by NIH staff upon receipt and
returned to the applicants without further consideration.
VII. REVIEW METHOD AND PEER REVIEW CRITERIA
Those applications that are complete and responsive may be
subjected to a triage by a peer review group to determine their
scientific merit relative to the other applications received in
response to this RFA. The NIH will withdraw from competition
those applications judged by triage to be noncompetitive and
notify the applicant and institutional business official.
Those applications judged to be competitive will be further
reviewed for scientific and technical merit by a Review
Committee convened by the Division of Research Grants, NIH. The
second level of review will be provided by the National Advisory
Allergy and Infectious Disease Council.
Awards will be based on scientific and technical merit
significance, originality, adequacy of research experience,
commitment, and time availability of the Principal Investigator
and other key personnel, adequacy of facilities, and reasonableness of
cost.
VIII. METHOD OF APPLYING
A. Receipt Date
The deadline for receipt of applications is April 22, 1991.
Applications received after this date will be considered as not
responsive to this RFA and will be returned without review.
B. General
1. The research grant application form PHS-398 (rev.
10/88) must be used in applying. These forms are available at
most institutional business offices and from the Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 499, 9000 Rockville
Pike, Bethesda, Maryland 20892.
Submit a signed, typewritten original of the application,
including the Checklist, and 23 signed, exact, single-sided
photocopies, in one package to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
2. TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH THIS
RFA:
a. The application form must have "DEVELOPMENT OF
MODELS FOR PLACENTAL AND PEDIATRIC METABOLISM, TOXICITY,
AND TRANSPORT OF anti-HIV DRUGS" (RFA AI-91-05) typed on
line 2 of the face page of the application form.
b. The RFA label provided with the instructions must be
affixed to the bottom of the face page. Failure to use
this label could result in delayed processing of your
application so that it may not reach the review committee
in time for review.
IX. INQUIRIES
Additional information may be obtained from:
Polly R. Sager, Ph.D.
Developmental Therapeutics Branch
Division of AIDS, NIAID
6003 Executive Blvd., Room 244P
Bethesda, MD 20892
Telephone: (301) 496-0636
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and Transplantation
Research. Grants are awarded under the authority of the Public
Health Service Act, Title IV, Section 301, as amended, Public
Law 78-410, Public Law 97-219, Public Law 99-158, Public Law 99-
500, and Report 99-711 to accompany HR 5233 and administered
under PHS grant policies and Federal Regulations 42 CFR 52 and
45 CFR Part 74. This program is not subject to the
intergovernmental review requirements of Executive Order 12372