CIMBALA@BIONET-20.ARPA (03/13/88)
From: Jim.Cassatt@BIONET-20.ARPA
Return-Path: <@CUNYVM.CUNY.EDU:CZJ@NIHCU.BITNET>
Received: from CUNYVM.CUNY.EDU by BIONET-20.ARPA with TCP; Fri 11 Mar 88 16:38:52-PST
Received: from NIHCU.BITNET by CUNYVM.CUNY.EDU ; Fri, 11 Mar 88 19:40:21 EST
To: science-resources@bionet-20.arpa
From: CZJ%NIHCU.BITNET@CUNYVM.CUNY.EDU
Date: Fri, 11 Mar 88 18:59:29 EST
From the NIH Guide to Grants and Contracts - March 4, 1988.
The whole things has items of interest so I am sending it out.
Jim Cassatt
--------------------------------------------------------------------
Vol. 17, No. 8, March 4, 1988
NOTICES
Presolicitation for: AIDS INFRASTRUCTURE PROJECTS.........(84/135)......... 1
Division of Research Resources
Index: RESEARCH RESOURCES
NOTIFICATION OF GRANT APPLICATION RECEIPT AND REFERRAL.....(138/159)........ 1
Public Health Service
Index: PUBLIC HEALTH SERVICE
NOTICE OF TRIAGE...........................................(161/188)........ 2
National Institute of Allergy and Infectious Diseases
Index: ALLERGY AND INFECTIOUS DISEASES
DATED ANNOUNCEMENTS (RFPs AND RFAs)
DEVELOPMENT OF MUTAGENESIS ASSAY USING TRANSGENIC MICE (RFP)....(194/246)... 2
National Institute of Environmental Health Sciences
Index: ENVIRONMENTAL HEALTH SCIENCES
MECHANISMS OF TOBACCO- AND ALCOHOL-RELATED CARCINOGENESIS (RFA)..(249/315).. 3
National Cancer Institute (804/1334)
Index: CANCER
THE NCI OUTSTANDING INVESTIGATOR GRANT..........................(321/410)... 4
National Cancer Institute
Index: CANCER
ONGOING PROGRAM ANNOUNCEMENTS
DETECTION OF NON-A, NON-B HEPATITIS VIRUS(ES) IN BLOOD (PA).....(416/497)... 5
National Heart, Lung, and Blood Institute
Index: HEART, LUNG, AND BLOOD INSTITUTE
ROLE OF GLYCATION IN AGING AND DIABETES (PA)....................(500/716)... 6
National Institute of Aging
National Institute of Diabetes and Digestive and Kidney Diseases
Index: AGING; DIABETES AND DIGESTIVE AND KIDNEY DISEASES
NOTICES
Presolicitation for: AIDS INFRASTRUCTURE PROJECTS
P.T. 36; K.W. 0780000, 0735000
Division of Research Resources
The purpose of this announcement is to alert the scientific community to a
proposed new program designed to enhance the nation's capabilities for AIDS
and AIDS-related research.
The Division of Research Resources plans to initiate a program of AIDS
infrastructure improvements. Grants would be made to non-Federal domestic
institutions ". . . for the repair, renovation, modernization and expansion
of existing facilities and the purchase of associated equipment" (House of
Representatives Report 100-498, Conference Report to accompany H.J. Res. 395,
page 278). Program guidelines are now being developed. Every effort will be
made to award these grants as rapidly as possible. All awards will be made
competitively.
The terms "repair," "renovation" and "modernization" are governed by the PHS
Grants Administration policies for alterations and renovations. The term
"expansion" means addition of new usable square footage to an existing
building (the additional space could not exceed the building's current net
usable square footage). Expansions proposed would be subject to the PHS
Grants Administration policies relating to construction. Funds could not be
used for the construction of wholly new facilities. Equipment and scientific
instrumentation associated with these infrastructure improvements may also be
requested.
To be eligible to apply for these awards, an institution must generally have
at least one active or pending PHS peer-reviewed AIDS or AIDS-related research
award.
It is anticipated that these awards will be in the range of $250,000 to
$1,000,000. No indirect costs would be paid. If the total cost of the
project exceeds $l,000,000, the applicant must provide assurance that the
additional funds are available.
Program guidelines and the Request for Applications will be available on or
about May 15, 1988. Receipt date for applications will probably be July 15,
1988; awards are planned for December 1, 1988. The number assigned to this
RFA is 88-RR-02.
To receive a copy of the program guidelines or RFA when available, please send
two self-addressed mailing labels to the address below. For further
information contact:
Mr. C. Alan Moore
Division of Research Resources
Building 31, Room 5B23
Bethesda, Maryland 20892
Telephone: (301) 496-0804
NOTIFICATION OF GRANT APPLICATION RECEIPT AND REFERRAL
P.T. 34; K.W. 1014002
Publis Health Service
Alcohol, Drug Abuse and Mental Health Administration
National Institutes of Health
The instructions to the "Application for Public Health Service Grant," Form
PHS 398 (revised 9/86), state on page 11 that "the PHS will send the principal
investigator/program director and the applicant organization the application's
number and the name, address, and telephone number of the executive secretary
of the initial review group to which it has been assigned." The purpose of
this NIH Guide notice is to inform applicants and organizations that the
Division of Research Grants, NIH, will use the address appearing in item 3e.
of the face page of the application to send this information to the principal
investigator/program director. Item 15., "Official in Business Office to be
Notified if an Award is Made," will be used to advise the applicant
organization. Therefore, those applicant organizations which prefer a locus
other than the business office may designate in item 15 whatever institutional
office should receive information regarding application status and Notices of
Grant Award.
1
NOTICE OF TRIAGE
P.T. 34; K.W. 1014002
National Institute of Allergy and Infectious Diseases
The NIAID announces its intent to perform triage in the review of applications
relevant to two recently announced Requests for Applications (RFAs). These
RFAs are:
RFA 88-AI-01, Programs of Excellence for Basic Research on AIDS, and RFA
87-AI-24, National Cooperative Drug Discovery Groups for the Treatment of
Acquired Immune Deficiency Syndrome (AIDS).
These RFAs were published in the October 16, 1987, and September 25, 1987,
issues, respectively, of the NIH Guide for Grants and Contracts.
Applications which are incomplete for review or are nonresponsive to the RFA
will be screened out and returned to the applicants without further
consideration. For each RFA, NIAID will convene a peer review group to
perform triage on the complete and responsive applications. The triage group
will determine the scientific merit of each application relative to the other
applications received in response to the RFA. The NIH will withdraw from
competition those applications judged by the peer group to be noncompetitive,
and will notify the applicant and the institutional official. Those
applications judged to be competitive will be further evaluated for scientific
and technical merit by scientific review committees especially convened for
this purpose.
DATED ANNOUNCEMENTS (RFPs AND RFAs)
DEVELOPMENT OF MUTAGENESIS ASSAY USING TRANSGENIC MICE
RFP AVAILABLE: NIH-ES-88-11
P.T. 34; K.W. 1002028, 0755010
National Institute of Environmental Health Sciences
The objective of this project is to develop and evaluate one or more _i_n _v_
mutagenesis assay systems to detect and quantitate gene mutations at a
precisely defined target sequence in a mouse exposed to a test chemical.
This project consists of three phases. During Phase I the contractor shall
construct and evaluate one or more suitable recombinant DNA vectors containing
an appropriate mutagenesis target. The contractor may utilize vectors,
mutagenesis target constructs or transgenic mouse strains described in the
scientific literature and available to the scientific community. Phase II is
concerned with the construction and characterization of transgenic animals and
consists of Tasks I and II. During Task I the contractor shall integrate a
vector carrying a mutagenesis target into the genome of a mouse embryo and
recover a mouse strain or strains transmitting the vector in a Mendelian or
sex-linked manner. During Task II, the contractor shall characterize
genetically a vector(s) carrying a mutagenesis target. Phase III of the
project is concerned with experimentally determining the potential of strains
produced in Phase II for use in mutagenesis assays and consists of Tasks I and
II. During Task I the contractor shall determine the level of the background
mutant frequency of the inserted mutagenesis target in various tissues and
organs of the transgenic mice. During Task II the contractor shall determine
the utility of the mutagenesis assay by measuring the induced mutant frequency
of the inserted mutagenesis target in various tissues and organs after
treatment with model mutagens.
The contract will cover a five-year performance period. The Government
estimates that the project will require approximately 1.25 professional person
years and 2 technical person years of effort each contract year.
This is an announcement of an anticipated request for proposals.
RFP NIH-ES-88-11 will be issued on or about April 1, 1988 with a closing date
for receipt of proposals of June 1, 1988.
Requests should reference RFP NIH-ES-88-11 and should be forwarded to:
2
National Institute of Environmental Health Sciences
Contracts Management Office, OAM
ATTN: Mary B. Armstead, Contracting Officer
79 T.W. Alexander Drive, 4401 Building
P.O. Box 12874
Research Triangle Park, North Carolina 27709
MECHANISMS OF TOBACCO- AND ALCOHOL-RELATED CARCINOGENESIS
OF THE ORAL CAVITY
P.T. 34; K.W. 0715035, 0404003, 0404019, 0755030
RFA AVAILABLE: 88-CA-08
National Cancer Institute
Application Receipt Date: May 23, 1988
Letter of Intent Receipt Date: April 8, 1988
The Division of Cancer Prevention and Control (DCPC), National Cancer
Institute (NCI), through the Organ Systems Program, announces the availability
of a Request for Applications (RFA) on the above subject.
Epidemiologic studies have demonstrated that there are at least two
tobacco-related causes of oral cavity cancer: a) snuff-dipping, and b) the
combination of chronic alcohol consumption and cigarette smoking. The latter
is a major risk factor for squamous cell cancer of the oral cavity. In view
of this epidemiologic lead, studies are needed on mechanisms by which alcohol
enhances oral cavity cancer induced by tobacco smoke. To test mechanisms
proposed, there is a need for development of suitable animal model systems
that mimic alcohol enhancement of tobacco-induced squamous cell cancer of the
oral cavity, as observed in man. Organ culture or cell culture systems could
also prove useful for investigating mechanisms of oral cavity carcinogenesis.
The use of smokeless tobacco, especially snuff-dipping, has increased
remarkably in the U.S. in recent years particularly among young males; surveys
for 1985 indicate that 16 percent of U.S. males between 12 and 25 years of age
used smokeless tobacco. Several scientific groups have concluded that
snuff-dipping is a cause of oral cancer in humans. Thus, research on the
mechanisms of oral cancer induction by local application of snuff or its
constituents is likewise necessary and timely.
The objective of this RFA is to invite investigators to use appropriate
experimental animal models, organ culture systems, or cell culture systems to
elucidate mechanism(s) by which tobacco use may increase the risk for squamous
cell cancer of the oral cavity. Studies should focus on mechanisms of
induction of oral cancer by (a) snuff-dipping, or (b) the combination of
chronic alcohol consumption and tobacco smoking. Appropriate studies could
include development of model systems for such studies, as well as research on
the mechanisms of oral cancer induction by smokeless tobacco, tobacco smoke,
or their carcinogenic constituents. Other novel approaches with appropriate
rationales are also encouraged.
Support for this program will be through the traditional NIH
investigator-initiated research grant (R01). It is anticipated that
approximately five awards, for project periods of up to three years, may be
made as a result of this RFA. Applicants are encouraged to submit a letter of
intent, and to consult with NCI program staff, before submitting an
application.
The RFA label (found in the 9/86 revision of application form PHS 398) 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 of
your application such that it will not reach the review committee in time for
review.
Copies of the RFA may be obtained by sending a written request to:
Dr. Elizabeth P. Anderson
Organ Systems Program
Division of Cancer Prevention and Control
National Cancer Institute
Blair Building - Room 717
Bethesda, Maryland 20892-4200
Telephone: (301) 427-8818
3
THE NCI OUTSTANDING INVESTIGATOR GRANT
P.T. 34; K.W. 0715035, 0710030
National Cancer Institute
Application Receipt Date: June 15
SUMMARY AND PURPOSE
The National Cancer Institute (NCI) will continue to accept applications for
the Outstanding Investigator Grant (OIG), the purpose of which is to provide
long-term support to experienced investigators with outstanding records of
research productivity. The OIG is intended to encourage investigators to
continue or embark on projects of unusual potential in cancer research.
Emphasis will be placed on evidence of recent substantive contributions (i.e.,
seminal ideas and innovative approaches to resistent problems) and the
potential for continued work of high caliber.
Special features of the OIG include: (1) seven year project periods; (2) the
delegation of authority to grantee institutions to carry over more than 20
percent of the direct cost authorization of OIGs from one budget period to the
next, with the approval of the NCI, and; (3) alleviation of the need to manage
more than one grant instrument through consolidation of the OIG principal
investigator's (PI's) current cancer-related and peer reviewed support.
ELIGIBILITY
Applications may be submitted only by domestic institutions on behalf of
investigators who have recently demonstrated outstanding research productivity
for at least five years. There are no age restrictions. Only United States
citizens, nationals or permanent residents may be presented as candidates for
this grant.
Applications will be accepted by the NCI only when they are cancer related as
defined by the Division of Research Grants (DRG) grant referral guidelines.
Investigators whose current research support is derived predominantly from
sources other than the NCI may not be eligible and are encouraged to discuss
their research objectives with appropriate NCI officials before applying.
The OIG PI is required to commit 75 percent of his/her time effort to the OIG
project and the institution sponsoring the OIG application is required to
commit itself to providing 25 percent of the investigator's support.
Applications which do not meet all of the above eligibility criteria or which
have not had approval from the NCI as exceptions to the above criteria will be
returned to the applicant.
HOW TO APPLY
o The date of receipt of all OIG applications will be June 15 of each
year. They will be processed for review at the earliest possible
meeting of the NCAB.
o Application for this award should be made on form PHS 398, revised
9/86 in accordance with instructions in this announce-ment. These
applications are available in the business or contracts offices of
most academic or research institutions, or from:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892
o The title "NCI OUTSTANDING INVESTIGATOR GRANTS' should be typed in
section 2.
o A letter indicating clear and continuing institutional commitment
to the applicant must either accompany the application or be
received separately before the NCI will begin the initial review
process.
INQUIRIES
All potential applicants for this award are advised that the full text of this
Program Announcement, containing currently applicable guidelines, is now
available and should be requested prior to submitting an application for the
June 15, 1988, receipt date.
4
Please direct inquiries for further information, and requests for copies of
the full announcement to:
Mrs. Barbara S. Bynum
Director
Division of Extramural Activities
National Cancer Institute
Building 31, Room lOA03
Bethesda, Maryland 20892
Telephone: (301) 496-5147
ONGOING PROGRAM ANNOUNCEMENTS
DETECTION OF NON-A, NON-B HEPATITIS VIRUS(ES) IN BLOOD
P.T. 34; K.W. 0755010, 0750010, 0715125, 1002045
National Heart, Lung, and Blood Institute
Application Receipt Dates: February 1, June 1, October 1
The Division of Blood Diseases and Resources (DBDR), National Heart, Lung, and
Blood Institute (NHLBI) encourages grant applications on the development of
serologic assays to detect non-A,non-B (NANB) hepatitis virus(es) in blood and
blood components for transfusion.
Posttransfusion hepatitis remains one of the most serious complications of
blood transfusion. The discovery, in 1968, that the viremic phase of serum
hepatitis (hepatitis type B, or HBV) could be detected by serologic assay
offered hope that virtually all infectious donors would one day be identified
and posttransfusion hepatitis prevented. Although the transmission of HBV is
almost completely preventable today, it is clear that another virus, namely,
NANB hepatitis virus, has supplanted HBV as the major cause of posttransfusion
hepatitis. NANB hepatitis virus has not yet been isolated and characterized
nor have specific serologic assays been developed to identify the agent(s).
There is evidence that more than one agent may cause NANB hepatitis. The
diagnosis of NANB hepatitis is presently based on the exclusion, by serologic
tests, of known etiologic agents of hepatitis. Serologic studies have shown
that the agent of NANB hepatitis is unrelated to hepatitis type A, hepatitis
type B, cytomegalovirus, Epstein-Barr virus, varicella-zoster, and herpes
simplex.
In the absence of specific serologic tests for the agent, an alternative
method for preventing posttransfusion NANB hepatitis is the use of
nonspecific, or surrogate, assays. Because of an association with NANB
hepatitis, elevated concentrations of alanine aminotransferase (ALT) and the
presence of antibody to HBV core antigen in the blood of donors are used as
indirect markers for screening for NANB hepatitis virus. The predictive value
of these assays in reducing posttransfusion hepatitis, however, is mediocre at
best and specific assays to detect the agent of antibody to the agent would be
preferable.
This program is described in the Catalog of Federal Domestic Assistance No.
13.839, Blood Diseases and Resources. 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.
This solicitation encourages the development of assays to detect antigens,
antibodies, or other components directly associated with NANB hepatitis virus
in blood and blood components. The tests should be simple to perform,
cost-effective, and applicable to the blood bank setting.
Applicants should use the regular research grant application (PHS 398). There
are three receipt dates each year for new applications: February 1, June 1,
and October 1. If applications are not available at the institution's
business office or central application control office, an individual copy may
be requested by writing to the Division of Research Grants (DRG), NIH. The
original and six copies of the application should be mailed to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, Maryland 20892**
5
All applications will be assigned by the DRG for review according to the NIH
process for regular research grant applications. Secondary review will be by
the National Heart, Lung, and Blood Advisory Council or other appropriate
National Advisory Council. Applications assigned to the National Heart, Lung,
and Blood Institute and recommended for approval will compete for available
funds with all other approved applications assigned to the NHLBI.
Inquiries should be directed to:
Dr. Luiz H. Barbosa
Blood Resources Branch
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 504
National Institutes of Health
Bethesda, Maryland 20892
Telephone: (301) 496-1537
ROLE OF GLYCATION IN AGING AND DIABETES
P.T. 34; K.W. 0710010, 0715075, 1003018, 0760005
National Institute on Aging and
National Institute of Diabetes and Digestive and Kidney Diseases
BACKGROUND
Glucose can react nonenzymatically with the amino groups of proteins and
nucleic acids to form Schiff bases and a series of other stable covalent
adducts (1, 2). This process, referred to as glycation, is part of the
Maillard reaction which can not only alter proteins and nucleic acids, but
also can lead to cross-linking. Cross-linking of long-lived proteins (e.g.
collagen and lens crystallins) increases as a function of age in both animals
and man and may be responsible in part for some of the physical changes that
occur in aging. One of the most characteristic changes in aging is a
progressive stiffness or rigidity of some tissues which may be caused by
cross-linking of collagen and elastin (3). Changes in peripheral nerves noted
in aging and diabetes could also be mediated by glucose-derived cross-links in
the neuronal microtubule protein, tubulin, through inhibition of the guanosine
triphosphate-dependent polymerization of nonaggregated tubulin to form
microtubles.
Recent research has shown that glycation products which accumulate in
long-lived proteins may be removed both by proteolytic turnover, or by the
specific uptake and degradation of glycated proteins by macrophages. It is
possible that either turnover or macrophagic action decreases with age
allowing the accumulation of glycation products in tissue. Glycation of
nucleic acids has also been reported. The role of these reactions in aging
processes remains to be explored.
Glycation may well be involved in the etiology of a number of age-related
diseases. The rigidity of structural proteins due to cross-linking may lead
to reduced elasticity in the cardiovascular system resulting in systolic
hypertension, decline of cardiac function, renal blood flow, vital lung
capacity and oxygen uptake. It has also been noted that low turnover proteins
treated with glucose can trap nonglycosylated proteins including albumin,
immunoglobulin (e.g. IgG), and low density lipoprotein (LDL). LDL trapping on
arterial walls could form the nidus for the formation of atherosclerotic
plaque. Increased glycation of osteocalcin with age has also been reported
(4), raising the possibility of a role for glycation of this protein in
osteoporosis. The proteins present in senile cataracts are reported, to be
significantly glycated, which offers a method to monitor and evaluate the
effects of glycation in the formation of cataracts.
Chronic hyperglycemia found frequently in diabetes may lead to increased
glycation of proteins, including short-lived proteins such as hemoglobin (5)
and albumin (6), and glycated proteins may be involved in development of the
complications of diabetes, e.g. neuropathy, nephropathy, and macroangiopathy.
Thus, diabetes in both animals and humans serves as a model system for the
study of glycation.
1. Bunn, H.F., Haney, D.N., Gabbay, K.H. and Gallop, P.M. (1975). Further
identification of the nature and linkage of the carbohydrate in hemoglobin
AIC. Biochem. Biophys. Res. Commun., 67: 103-109.
2. Koenig, R. J., Blobstein, S. H., and Cerami, A. (1977). Structure of
carbohydrate of hemoglobin AIC. J. Biol. Chem., 252: 2992-2997.
6
3. Monnier, V.M., Kohn, R.R. and Cerami, A. (1984). Accelerated age-related
browning of human collagen in diabetes mellitus. Proc. Natl. Acad. Sci.
USA, 81: 583-587.
4. Gundberg, C.M., Anderson, M., Dickson, I. and Gallop, P.M. (1986).
"Glycated" Osteocalcin in human and bovine bone. The effect of age. J. Biol.
Chem., 261: 14557-14561.
5. Bunn, H.F., Gabbay, K.H., and Gallop, P.M. (1978). The glycosylation of
hemoglobin: Relevance to diabetes mellitus. Science, 200: 21-27.
6. Guthrow, C.E., Morris, M.A., Day, J.F., Thorpe, S.R. and Baynes, J.W.
(1979). Enhanced nonenzymatic glycosylation of human serum albumin in
diabetes mellitus. Proc. Natl. Acad. Sci. USA, 76: 4258-4261.
GOALS AND SCOPE
The goal of this announcement is to encourage research on the nonenzymatic
glycosylation of macromolecules, especially proteins and nucleic acids, and
the role those glycation products play in diabetes and aging processes. This
research offers a unique opportunity for interdisciplinary collaboration in
the areas of biochemistry, analytical and organic chemistry, immunology, food
science and nutrition, epidemiology, cell biology, aging, and diabetes, and
the NIA and NIDDK encourage collaborative proposals from clinical and
experimental gerontologists, geriatricians, diabetologists, and
epidemiologists.
SPECIFIC OBJECTIVES
The NIA and NIDDK seek applications to test hypotheses and elucidate
mechanisms including, but not limited to, the following three general areas:
o Structure of glycated products, mechanisms of their systems, and
the role of these glycation products in aging, and the long term
complications of diabetes.
o The relationships between glycation products and the etiology of
age-related diseases, such as cardiovascular disease, cancer,
cataracts, arthritis, osteoporosis, etc.
o The relationship between control of diabetes and the reversible and
irreversible formation of these glycation products.
Although studies with human cells and tissues are preferred for biological
studies, use of other vertebrates may be desirable where shorter life spans
and more defined genetic systems are an advantage. Therefore, the NIA
supports several colonies of animals and an Aging Cell Repository for use in
such research projects. The NIDDK supports a contract for supply of BB rats
for use as a model for Type 1 diabetes. Applicants interested in using these
resources should contact the following persons:
Contact person for aging rats and mice:
Ms. Jane Soban
Molecular and Cell Biology Branch
Building 31, Room 5C21
National Institute on Aging, NIH
Bethesda, Maryland 20892
Telephone: (301) 496-6402
Contact person for cultured cells:
Dr. Arthur E. Greene
Aging Cell Repository
CORIELL Institute for Medical Research
Camden, New Jersey 08103
Telephone: (609) 966-7377
Contact person for BB diabetic rats:
Dr. Robert E. Silverman
DPB/DEMD/NIDDK
National Institutes of Health
Westwood Building, Room 626
Bethesda, Maryland 20892
Telephone: (301) 496-7888
7
Contact person for Primates:
Dr. DeWitt Hazzard
Molecular and Cell Biology Branch
Building 31, Room 5C19
National Institute on Aging, NIH
9000 Rockville Pike
Bethesda, Maryland 20892
Telephone: (301) 496-6402
The primary mechanisms for support of this program are:
o Research grant (R01)
o Program Project Award (P01)
o First Award (R29)
o Career grants, which include:
Special Emphasis Research Career Award (K01) in Nutritional
and Metabolic Factors in Aging (NIA only)
Research Career Development Award (K04)
Clinical Investigator Award (K08)
REVIEW PROCEDURES
Applications will be reviewed by regular study sections of the NIH, or in the
case of P01's and K08's by the review group of the relevant Institute, in
accordance with the usual NIH peer review procedures, based on scientific
merit. Following study section review, the applications will be evaluated by
the appropriate National Advisory Council.
METHOD OF APPLYING
Applications should be submitted on the PHS 398 application form (Rev. 9/86),
and will be accepted at regular application deadlines. There are no set-aside
funds for funding these applications. If your institution does not have NIH
research grant application kits, copies may be obtained by writing:
Office of Grant Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892
Telephone: (301) 496-7441
Forward the original plus six (6) copies of the completed application to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892**
Potential applicants interested in obtaining further information can call:
Dr. Ann Sorenson
Health Scientist Administrator, Geriatrics Branch
National Institute on Aging
National Institutes of Health
Bethesda, Maryland 20892
Telephone: (301) 496-1033
Dr. Huber R. Warner
Chief, Molecular and Cell Biology Branch
National Institute on Aging
National Institutes of Health
Bethesda, Maryland 20892
Telephone: (301) 496-6402
Dr. Elaine Collier
Assistant Director, Diabetes Research Program
National Institute of Diabetes and Digestive and
Kidney Diseases
National Institutes of Health
Westwood Building, Room 622
Bethesda, Maryland 20892
Telephone: (301) 496-7731
8
**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
9
FULL TEXT OF RFAs FOR ONLINE ACCESS
MECHANISMS OF TOBACCO AND ALCOHOL RELATED CARCINOGENESIS
OF THE ORAL CAVITY
RFA AVAILABLE: 88-CA-08
P.T. 34; K.W. 0715035, 0404003, 0404019, 0755030
National Cancer Institute
Application Receipt Date: May 23, 1988
The Division of Cancer Prevention and Control of the
National Cancer Institute (NCI), through the Organ
Systems Program, invites research grant applications
from interested investigators to study the mechanisms of
oral cavity cancers. Epidemiologic studies have
demonstrated that there are at least two tobacco related
causes of oral cavity cancer: a) snuff-dipping, and
b) the combination of chronic alcohol consumption and
cigarette smoking. Although there have been many
mechanistic studies concerning tobacco carcinogenesis,
studies aimed at the mechanisms by which tobacco in
combination with alcohol induce cancer, especially with
the oral cavity as the target tissue, have been limited.
This solicitation (RFA) is being used to encourage
investigator initiated research projects to develop
appropriate animal models or cell/organ culture systems
and to explore mechanisms of tobacco and alcohol
combinations in oral cavity carcinogenesis. This is an
area of special programmatic interest to the National
Cancer Institute. Proposals funded under this RFA will
be supported through the traditional grant-in-aid in
accordance with applicable policies and requirements of
the Public Health Service and the National Institutes of
Health.
This RFA is for a single competition with a specified
deadline of May 23, 1988 for receipt of applications.
All applications which are responsive to this RFA will
be reviewed by the same National Cancer Institute
special review committee. A letter of intent is
encouraged but not required (see Section V.A.).
Applications should be prepared on PHS Form 398 (revised
9/86) and submitted in accordance with the aims and
requirements described in the following sections:
I. BACKGROUND INFORMATION
II. RESEARCH OBJECTIVES AND SCOPE
III. MECHANISM OF SUPPORT
IV. REVIEW PROCEDURES AND CRITERIA
V. METHOD OF APPLYING
VI. INQUIRIES
I. BACKGROUND INFORMATION
Epidemiologic studies have demonstrated that there are
at least two tobacco related causes of oral cavity
cancer: a) snuff-dipping, and b) the combination of
chronic alcohol consumption and cigarette smoking. The
latter (b) is a major composite risk factor for squamous
cell cancer of the oral cavity (1-4). For example, the
relative risk for developing oral cavity cancer among
individuals consuming seven or more ounces of alcohol
per day and greater than one pack of cigarettes per day
was found to be 24 times greater than that of
nondrinkers, nonsmokers, while heavy drinking among
smokers further increased the oral cancer risk two- to
four-fold (4). It has been estimated that as much as
50% of oral cancer in the U.S. is associated with heavy
drinking.
In view of this epidemiologic lead, studies are needed
on the mechanisms by which alcohol enhances induction of
oral cavity cancer by tobacco smoke. Several theories
have been advanced to explain the epidemiologic
observations, including the following: 1) Alcohol might
act as a solvent, increasing the penetration of
carcinogens contained in tobacco smoke into susceptible
cells of the oral cavity. Although this theory appears
to be attractive, there are limited data supporting it
at the present time. 2) Chronic alcohol consumption is
known to induce microsomal enzyme activities, including
cytochrome P-450 isozymes. Some of these enzymes are
the same as those which catalyze the metabolic
activation of tobacco smoke carcinogens such as
N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine
(NPYR), N'-nitrosonornicotine (NNN), and benzo[a]pyrene,
and consequently chronic alcohol consumption could lead
to increased metabolic activation of these compounds.
3) Alcohol can act as a competitive inhibitor of hepatic
carcinogen metabolism and consequently might cause a
change in pharmacokinetics resulting in increased
exposure of extrahepatic tissues to carcinogens. 4) The
nutritional deficiencies associated with chronic alcohol
consumption might lead to alterations of epithelial cell
biochemistry or immune status associated with increased
susceptibility to carcinogenesis. Such nutritional
deficiencies could include vitamins A, E, B2, zinc, and
iron. 5) Alcohol consumption could lead to increased
intracellular levels of oxidants, resulting in DNA
damage by lipid peroxidation products or related
mechanisms. Combinations of the above phenomena, as
well as other effects of chronic alcohol consumption,
could be important in oral carcinogenesis.
Bioassays designed to test the above hypotheses and/or
to reproduce in experimental animals the enhancing
effect of alcohol on tobacco tumorigenicity, as observed
in man, have not been uniformly successful, especially
with respect to squamous cell cancer of the oral cavity.
Ethanol increased the number of tumors per animal
induced in the Syrian golden hamster cheek pouch by the
experimental carcinogen 7,12-dimethylbenz[a]-
anthracene (DMBA) (5). This study was limited, however,
by the relatively small number of animals used; in
addition, DMBA is not known to be present in tobacco
smoke and its mechanism of action may be distinct from
carcinogens that are found in tobacco smoke. Several
studies have examined the effects of ethanol on
nitrosamine carcinogenesis (e.g., 6-8). The results of
these studies vary with the protocol employed, the
species, and the nitrosamine used. Enhancing effects of
varying magnitudes and/or target tissue shifts have been
observed in experiments with NPYR, NNN, NDMA, N-
nitrosodiethyl- amine, and N-nitrosodipropylamine.
However, the oral cavity was not the target tissue in
any of these experiments. Thus, a need exists for the
development of a suitable animal model for reproducing
the alcohol enhancement of tobacco induced squamous cell
cancer of the oral cavity, as observed in man.
The use of smokeless tobacco, especially snuff-dipping,
has increased remarkably in the U.S. in recent years,
particularly among young males. In 1985, at least 12
million people used smokeless tobacco, in the form of
chewing tobacco or moist snuff; surveys indicate that
16% of U.S. males between 12 and 25 years of age used
smokeless tobacco (9). The practice of snuff dipping,
placing moist snuff between the cheek and gum, has
become especially popular. Production of moist snuff
has increased markedly since 1981, reaching almost 40
million pounds in the U.S. in 1985. Recently, a Working
Group of the International Agency for Research on
Cancer, an Advisory Committee to the U.S. Surgeon
General, and an NIH Consensus Development Conference
have evaluated the literature; all three groups
concluded that snuff-dipping causes oral cancer in
humans (1a, 9, 10). In one study, there was a four-fold
increased risk of oral-pharyngeal cancer among
nonsmoking white women who dipped snuff. For long term
chronic snuff users, there was nearly a 50-fold increase
in risk for cancers of the gum and buccal mucosa (11).
In view of these data, research on the mechanism of oral
cancer induction by local application of snuff or its
constituents is necessary and timely.
The most abundant known carcinogens in snuff are the
tobacco specific nitrosamines. Two of these compounds,
NNN and 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone
(NNK) are strong carcinogens in experimental animals.
Snuff also contains benzo[a]pyrene and 210Po but in
lesser amounts than the tobacco specific nitrosamines.
Application of NNN and NNK to the oral cavity of F344
rats resulted in induction of local tumors. However,
tumor incidence was decreased when NNN and NNK were
applied together with a water extract of snuff. The
reason for this apparent inhibitory effect of snuff
extract on NNN and NNK tumorigenicity in the oral cavity
is not known. Extensive bioassays of tobacco and its
extracts have been carried out in various experimental
animal systems. Positive results have been obtained
only when snuff was repeatedly inserted in a surgically
created canal in the rat lip; however, the incidence of
tumors was not statistically significant. In contrast,
treatment of hamsters with snuff and herpes simplex
virus induced a high incidence of squamous cell
carcinoma in the buccal pouch. These data indicate that
synergistic effects are important in oral cancer
induction by snuff.
The detection of preneoplastic changes in the oral
epithelium of experimental animals or humans exposed to
tobacco products may be another approach to assessing
the mechanism of tobacco related oral carcinogenesis.
For example, recent studies have shown that foci
positive for gamma-glutamyl transpeptidase can be
detected in the early stages of oral tumor induction by
DMBA or N-nitroso-benzylmethylamine in the Syrian golden
hamster cheek pouch (12). These foci were also detected
in precancerous lesions and oral carcinoma of
individuals with a history of tobacco smoke exposure and
alcohol consumption. In general, attempts to duplicate
intraoral mucosal changes of leukoplakia and other forms
of hyperplasia, with and without dysplasia, have not
been well documented. The majority of oral cavity
carcinomas are thought to arise in damaged mucosa, as
evidenced by either epithelial hyperplasia and/or
epithelial atrophy with dysplasia. The former is
commonly manifested as leukoplakic and the latter as
erythroplakic mucosal appearance. Many, if not all,
oral cavity squamous carcinomas appear to be preceded by
mucosal alterations with prominent cytologic dysplasia.
Epithelial dysplasia as evidenced by premature
keratinization or dyskeratosis has been reproduced in
hamsters. Micronuclei in exfoliated oral cavity cells
have also been measured in populations of smokers and
drinkers.
Cell culture approaches may also be useful for
investigating mechanisms of oral cavity carcinogenesis.
A recent study has shown that in vivo exposure of
hamster cheek pouch epithelium to carcinogens caused a
suppression in the number and growth of keratinocyte
colonies in culture, and appeared to induce or select
for a population of keratinocytes with unique colony
morphology (10).
References:
1. International Agency for Research on Cancer, IARC
Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans. a. Vol 37, Tobacco Habits other
than Smoking Betel-Quid and Areca-Nut Chewing and Some
Related Nitrosamines. IARC, Lyon, France, 1985,
pp 37-140; b. Vol 38, Tobacco Smoking, Idem, 1986,
pp 298-300.
2. US Dept of Health and Human Services, The Health
Consequences of Smoking; Cancer. A Report of the
Surgeon General, US Government Printing Office,
Washington, DC, 1982, pp 88-90.
3. Cann CI, Fried MP, and Rothman KJ. Epidemiology of
squamous cell cancer of the head and neck. Otolaryngol
Clin North Amer 18: 1-22, 1985.
4. McCoy GD, and Wynder EL. Etiological and preventive
implications in alcohol carcinogenesis. Cancer Res 39:
2844-2850, 1979.
5. Freedman A and Shklar G. Alcohol and hamster buccal
pouch carcinogenesis. Oral Surg, Oral Med, Oral Path
46: 794-805, 1978.
6. Castonguay A, Rivenson A, Trushin N, Reinhardt J,
Stathopoulos A, Weiss CJ, Reiss B, and Hecht SS.
Effects of chronic ethanol consumption on the metabolism
and carcinogenicity of N'-nitrosonornicotine in F344
rats. Cancer Res 44: 2285-2290, 1984.
7. Griciute L, Castegnaro M, Bereziat JC, and Cabral
JRP. Influence of ethyl alcohol on the carcinogenic
activity of N-nitrosonornicotine. Cancer Lett 31:
267-275, 1986.
8. McCoy GD, Hecht SS, and Furuya K. The effect of
chronic ethanol consumption on the tumorigenicity of N-
nitrosopyrrolidine in male Syrian golden hamsters.
Cancer Lett 33: 151-159, 1986.
9. Advisory Committee to the Surgeon General. The
Health Consequences of Using Smokeless Tobacco. US Dept
of Health and Human Services, NIH Publication No
86-2874, 1986, pp 5-28, 33-47.
10. NIH Consensus Development Conference, Health
Implications of Smokeless Tobacco Use. J Amer Med Assoc
255: 1045-1048, 1986.
11. Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, and
Fraumeni JF Jr. Snuff-dipping and oral cancer among
women in the southern United States. New Eng J Med 304:
745-749, 1981.
12. Polverini PJ, and Solt DB. Effect of in vivo
carcinogen exposure on colony formation and growth of
hamster buccal pouch keratinocytes in culture. Lab
Invest 54: 432-441, 1986.
II. RESEARCH OBJECTIVES AND SCOPE
The specific objectives of this RFA are to use
appropriate experimental animal models, organ culture
systems, or cell culture systems to elucidate the
mechanism(s) by which tobacco use increases the risk for
squamous cell cancer of the oral cavity. Studies should
focus on the induction of oral cancer by (a) snuff-
dipping, or (b) the combination of chronic alcohol
consumption and tobacco smoking.
Appropriate studies could include the development of
animal models, or cell/organ culture systems for
investigating the mechanisms of oral cavity cancer
induction by tobacco and alcohol. Thus the development
of a reproducible animal model of oral cancer, in which
the carcinogen is tobacco smoke or its condensate, or a
compound or compounds present in tobacco smoke, and in
which tumor incidence is enhanced by alcohol, would be
most useful. Ideally, the model should have essential
characteristics in common with the human setting. In
addition, an animal model for induction of oral cavity
cancer by snuff is needed for further investigations of
snuff-induced carcinogenesis of the oral cavity. Animal
models which show precursor mucosal changes associated
with cancer development and similar to those observed in
humans would also be useful. Cell culture and/or organ
culture systems which undergo changes indicative of
neoplastic development in response to tobacco or tobacco
smoke and its constituents are needed. Such models
might focus on tumor initiation, tumor promotion, or
cocarcinogenesis.
Appropriate studies might also include the effects of
alcohol on the metabolic activation or DNA binding of
carcinogens present in tobacco smoke or on subsequent
DNA repair; however, it is important that these kinds of
studies be carried out in tissues or cells of the oral
mucosa. The effects of alcohol on oncogene activation
or related changes induced in oral tissues by tobacco
smoke constituents would also be of interest. Further
studies are needed on the relationship of the
nutritional deficiencies and oxidant imbalances
associated with alcohol consumption and the
susceptibility of oral tissues to carcinogenesis by
tobacco smoke and its constituents. Investigations of
the effects of alcohol on the penetration and absorption
of tobacco smoke and its constituents through the oral
mucosa, and on the pharmacokinetics of tobacco smoke
constituents, as it relates to oral cavity cancer, would
also be useful.
In addition to the development of animal models or
culture systems, further research on the mechanisms of
oral cancer induction by snuff is needed. Such studies
might focus on synergistic effects in snuff
carcinogenesis leading to the identification of factors
such as virus infection or tobacco constituents, which
either enhance or inhibit oral cancer induction by
snuff. These investigations should focus on the
mechanisms of these potential synergistic effects.
It is not implied that investigators should pursue all
of the above experimental suggestions or even these
examples only; other novel approaches with appropriate
rationales are encouraged. There is no requirement to
study carcinogenesis both for alcohol and tobacco, as
well as for snuff; these objectives can be pursued
either independently or jointly. In either case,
studies should be well focused, pose appropriate
hypotheses or biological questions and be oriented
toward elucidating mechanisms.
III. MECHANISM OF SUPPORT
The mechanism of support for this program will be
through the traditional NIH investigator initiated
research grant (R01). Policies that govern research
grant programs of the NIH will prevail. Awards may be
made to non-profit and profit organizations for a period
of support of up to three years under this RFA. This
type of initiative is used when NCI, with the
concurrence of a Board of Scientific Counselors, wishes
to stimulate investigator interest in an important and
opportune area of research.
It is anticipated that approximately five awards for
project periods of three years will be made at a total
cost of $750,000 for the initial year's funding. This
RFA solicitation is a single competition and has one
specific deadline for receipt of applications. Revised
applications or subsequent renewal applications would be
reviewed in competition with other R01 grants in the
regular NIH grant review system. Although this program
is provided for in the financial plans of the NCI,
awards are contingent upon availability of funds for
this purpose and the receipt of applications of high
scientific merit.
IV. REVIEW PROCEDURES AND CRITERIA
A. Review Method
Applications will be reviewed by NCI staff for
responsiveness to this announcement. If an application
is judged to be unresponsive to this RFA, the applicant
will be contacted and given the option of submitting it
for consideration with all other unsolicited grant
applications received by NIH for that review cycle or
having it returned to the applicant institution.
Applications that are responsive to the goals of this
RFA will be reviewed in competition with each other, in
accordance with the stated review criteria, by the usual
NIH peer review procedures. The applications will be
initially reviewed for scientific merit by a special
review committee convened by the Division of Extramural
Activities (DEA), National Cancer Institute, National
Institutes of Health. The NCI funding decision will be
based on the recommendations of the scientific peer
review group as well as on program relevance, together
with final review by the National Cancer Advisory Board.
Minimal requirements for application are the following:
o Studies that address the objectives of the RFA, with
appropriate plans for focusing attention on the
priorities of emphasis requested in the RFA.
o Expertise of the investigators in experimental
carcinogenesis; availability of the model system(s)
proposed for the study of oral cavity cancer.
Applications received after the May 23, 1988 receipt
deadline will be returned to the applicant.
B. Review Criteria
Evaluation of the applications for scientific merit will
apply standard NIH peer review procedures and will
include assessment of the following factors:
o Assessment of the importance of the proposed studies
for the objectives of the RFA.
o Scientific merit and originality of the proposed
research; adequacy of the experimental design; and
feasibility and familiarity with the proposed
techniques demonstrated with preliminary data and/or
publications.
o Adequacy of the proposed model system(s) and
experimental materials and their appropriateness for
the study of oral cavity cancer.
o Research experience and competence of the Principal
Investigator to direct and conduct the proposed
studies; adequacy of appropriate personnel,
facilities, and resources.
o Adequacy of practices, procedures, and facilities
relative to laboratory safety procedures.
o Adequacy of animal welfare practices and procedures.
o Appropriateness of the requested budget relative to
the work proposed.
V. METHOD OF APPLYING
Application receipt date: May 23, 1988
A. Letter of Intent
Prospective applicants are asked to submit a one-page letter
of intent, which includes the RFA number, to Dr. Elizabeth
P. Anderson (see Sect VI for address). This letter of
intent should be submitted by April 8, 1988, and should
provide the title of the proposal, the name and address of
the principal investigator, the names of other personnel and
the participating institutions. The Institute requests a
letter of intent in order to provide an indication of the
number of applications to be received. In addition, should
it appear that the potential applicant has misunderstood a
specific solicitation or opted for an inappropriate funding
mechanism, NCI staff will respond to such letters. The
letter of intent is not binding; it will not enter into the
review of any proposal subsequently submitted, nor is it a
mandatory requirement for the submission of the application.
B. Format of Application
Applications must be submitted on Form PHS 398 (Revised
9/86), which is the application form for the traditional
research project grant. The RFA label available in the
9/86 revision of Application Form 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. Application kits are available at most
institutional business and grant-contract offices, or
may be obtained from the Division of Research Grants
(DRG), NIH, Bethesda, Maryland 20892-4500. The
conventional presentation format and details applicable
to regular research grant applications should be
followed, and the requirements specified under Review
Criteria (see Section IV.B.) must be fulfilled. The
number and title of this RFA should be typed in
Section 2 on the front page of the application as
follows: "In response to RFA 88-CA-08: Mechanisms of
Tobacco and Alcohol Related Carcinogenesis of the Oral
Cavity."
C. Application Procedures
The completed original application and four (4) copies
should be sent or delivered to:
Division of Research Grants
National Institutes of Health
Westwood Building - Room 240
Bethesda, Maryland 20892-4500**
Two (2) copies should be sent or delivered to:
Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building - Room 848
5333 Westbard Avenue
Bethesda, Maryland 20892-4500
To ensure their review, applications should be received
by May 23, 1988. Applications received after that date
will be returned to the applicant.
VI. INQUIRIES
Requests for further information should be directed to:
Dr. Elizabeth P. Anderson
Organ Systems Program
Division of Cancer Prevention and Control
National Cancer Institute
Blair Building - Room 717
Bethesda, Maryland 20892-4200
Telephone: 301/427-8818
This program is described in the Catalog of Federal
Domestic Assistance No. 13.393. Grants will be awarded
under the authority of the Public Health Service Act,
Title III, Section 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 inter-
governmental review requirements of Executive Order
12372 for Health Systems Agency review.
-------