Full Text DK-94-007

HORMONAL REGULATION OF BREAST-SPECIFIC GROWTH FACTORS

NIH GUIDE, Volume 22, Number 37, October 15, 1993

RFA:  DK-94-007

P.T.


Keywords: 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  January 21, 1994
Application Receipt Date:  February 18, 1994

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research grant applications to
investigate the biology, physiology, and pathophysiology of systemic
hormones and their role in regulation of growth factors and cytokines
and their receptors in both normal and abnormal endocrine regulatory
activity associated with breast tissue.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Hormonal Regulation of Breast-Specific Growth
Factors, is related to the priority areas of cancer and maternal
health.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Minority individuals and women are encouraged to submit as Principal
Investigators.  Foreign institutions are not eligible for First
Independent Research Support and Transition (FIRST) (R29) awards.

MECHANISM OF SUPPORT

Support of this program will be through the NIH research project
grant (R01) or FIRST (R29) awards.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  Awards will be administered under PHS grants
policy as stated in the PHS Grants Policy Statement and this RFA.

This RFA is a one-time solicitation.  Generally, future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.  The total requested project period
for applications submitted in response to this RFA may not exceed
four years for R01s and five years for R29s.  A maximum of three
years may be requested for foreign awards.  The earliest possible
award date will be September 30, 1994.

FUNDS AVAILABLE

For FY 1994, $2,500,000 will be committed to fund applications
submitted in response to this RFA.  It is anticipated that up to 12
awards will be made.  However, this funding level is dependent upon
the receipt of a sufficient number of applications of high scientific
merit.  Applicants must limit their requests to not more than
$160,000 direct costs for the initial budget period.  Although this
program is provided for in the financial plans of the NIDDK, the
award of grants pursuant to this RFA is also contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Breast tissues are significant targets of endocrine actions.  A
number of hormones such as estrogens, progestins, growth hormone,
hydrocortisone, insulin, prolactin and other members of the
steroid/thyroid/vitamin hormone superfamily promote in vitro growth
of both non-malignant and malignant human breast tissue.  Many
systemic hormones interact with and/or regulate other intermediates,
including growth factors and cytokines to provide multiple
stimulatory signals on tissues and cells affecting the growth and
function of sensitive breast structures.

Although the role(s) of locally active hormones in breast tissue
growth, regulation, disease, and/or neoplasia is not fully
understood, it is clear that systemic hormones do stimulate tissues
to synthesize and release the growth factors (e.g., growth hormone
and insulin-like growth factor-I).  In other instances, growth
factors have been reported present in breast tissue, including
gastrin-releasing peptide (GRP), epidermal growth factor (EGF), and
insulin-like growth factors (IGF).  In addition, EGF is capable of
stimulating in vitro growth of breast stromal elements, while IGF-I
and TGF appear to mediate certain growth effects of some estrogens on
breast epithelium.  Still other reports suggest that in cultured
breast tissue, stromal elements from either benign or malignant
lesions may express a number of mitogenic growth factors including
platelet-derived growth factor (PDGF-A chain), fibroblast growth
factors (FGF), transforming growth factors and insulin-like growth
factors.  In addition, breast stromal fibroblasts secrete a form of
interleukin-6 (IL6) that stimulates the ability of some human breast
cell lines to convert estrone (E1) to the more biologically active
17-beta-estradiol (E2) by an increase in reductive E2- oxidoreductase
(EOR) activity.

Recent molecular cloning studies have revealed that some growth
factor receptors have significant homologies with cellular
proto-oncogenes and/or viral oncogenes (e.g., PDGF and v-sis), whose
inappropriate expression and/or altered function play roles in the
process of breast tissue growth.  Moreover, oncogenes and
proto-oncogenes often appear to represent altered forms of normal
cellular receptors for systemic hormones and/or growth factors whose
expression is required for the normal functioning of the same tissues
(e.g., EGF and the HER2/neu oncogene).  Some hormones, growth
factors, and/or cytokines also have cognate binding proteins that may
play a role in mediating or regulating their physiological effects
and may play a role in various steps associated with cell growth,
differentiation and metabolism.

With better understanding of the possible interactions among
hormones, growth factors, cytokines, or their cognate receptors it
may be possible to exploit the respective biologic activities of
these substances or their antagonists in developing new therapeutic
and preventative agents.  For instance, growth factor or cytokine
receptor and/or binding proteins and protein segments may have
potential therapeutic value as great or greater than that of the
cognate cytokines and growth factors.

Clearly, further understanding of the role of systemic hormones in
the regulation and interaction of growth factors, cytokines, and
homologous proto-oncogenes and other endocrine factors with roles in
signal transduction in normal and diseased breast tissue structure
and function, is required.  The rapidly growing clinical applications
of the biologic activities of these substances only magnifies this
imperative.

Scope

Some examples of research topics that would be considered responsive
to this solicitation include the following:

o  the regulation, by systemic hormones, of the expression and/or
release of growth factors, cytokines, or cognate receptors in breast
tissue, in vivo or in vitro

o  alterations in the expression, production, or function of hormone
receptors after stimulation of breast tissues by growth factors or
cytokines

o  hormonal interactions with DNA/RNA regulatory elements (e.g.,
HREs) involving the production of growth factors, cytokines, and/or
cognate receptors (e.g., alternate splicing, tissue specificity, or
altered forms) in response to circulating hormones

o  identification of the effects of hormones on various
proto-oncogene/receptors for growth factors or cytokines; mutations
that cause dysregulated endocrine function

o  role(s) of systemic hormone, growth factor and cytokine receptors
and/or their homologues (e.g., proto-oncogenes) in ordered and
disordered regulation of gene expression in breast tissue

o  mechanism of action of hormone, growth factor or cytokine
receptors in effecting signal transduction in breast; interaction(s)
with other signal transduction pathways (i.e., cross-talk) and
altered interactions in disease, including altered
endocrine/paracrine/autocrine communication

o  identification and functional significance of genes whose
expression is regulated by signal transduction through systemic
hormone, growth factor, and cytokine receptors on breast tissues

o  role and mechanism of action of analogues and/or antagonists to
hormones/growth factors/cytokines or their receptors in treatment of
breast dysplasia or neoplasia

o  identification and characterization of orphan receptors in breast
epithelium with functions related to those of known receptor
tyrosine/serine kinases or phosphatases and/or members of the
steroid/thyroid/vitamin hormone superfamily.

These areas of interest are not listed in any order or priority.
They are only suggested examples of areas of research.  Applicants
are encouraged to propose other areas that are related to the
objectives and scope described above.  Applications that propose
issues of age-related changes (e.g., menopause) or reproductive
biology will be considered non-responsive to this RFA and will have
standard DRG referral guidelines relevant to NIA or NICHD,
respectively, applied.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample is appropriate for the scientific objectives of the
study.  This information must be included in the form PHS 398 (rev.
9/91) in Item 4 (Research Design and Methods) of the Research Plan
AND summarized in Item 5, Human Subjects.  Applicants are urged to
assess carefully the feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes that it
may not be feasible or appropriate in all research projects to
include representation of the full array of United States
racial/ethnic minority populations; i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders,
Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded. However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies. NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 21, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be 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 helpful in planning for the review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 594-7515
FAX:  (301) 594-7503

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892;
telephone (301) 710-0267.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition,
the RFA title and number must be typed on line 2a of the face page of
the application form and check the YES box.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by February 18, 1994.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  However, it is
allowable to submit the same project as both an R01 and as a
component project of a program project, with the proviso that only
one could be funded.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of substantial revisions of applications previously
reviewed.  Such applications must not only include an introduction
addressing the previous critique, but also be responsive to this RFA.

FIRST Award applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST Award applications submitted without the required number of
reference letters will be considered incomplete and will be returned
without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be initially reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK staff function.  If the application is not responsive
to the RFA, NIDDK staff will contact the applicant to determine
whether it should be returned to the applicant or held until the next
regular receipt date and reviewed in competition with all other
applications.

If the number of applications is large compared to the number of
awards to be made, a preliminary scientific peer review may be
conducted and applications withdrawn from further competition when
they are not competitive for the award.  The NIDDK will notify the
applicant and institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened by
the NIDDK for this RFA.  Following this review, the applications will
be given a second level review by the NIDDK Advisory Council, unless
not recommended for further consideration by the initial review
group.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

o  for foreign applications: uniqueness of research such that it can
be performed only outside of the United States.

AWARD CRITERIA

Funding decisions will be made based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are
encouraged.  The opportunity to clarify any issues or questions from
potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

W. Lorenzo Jackson, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 594-7576
FAX:  (301) 594-9011

Inquiries regarding fiscal matters may be directed to:

Ms. Kim Law
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649D
Bethesda, MD  20892
Telephone:  (301) 594-7543

Schedule

Letter of Intent Receipt Date:  January 21, 1994
Application Receipt Date:       February 18, 1994
Initial Review:                 June 1994
Second Level Review:            September 1994
Anticipated Date of Award:      September 30, 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.847.  Awards are made 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) and administered
under PHS grants 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.

.

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