Release Date:  November 25, 1998

RFA:  MH-99-003


National Institute of Mental Health

Letter of Intent Receipt Date: January 17, 1999
Application Receipt Date: February 17, 1999


The National Institute of Mental Health (NIMH) is committed to the creation of
interdisciplinary research to advance understanding of complex mental disorders. 
To facilitate this commitment, NIMH invites proposals for the formation of cross-
disciplinary networks of scientists interested in the role of hypothalamic-
pituitary-adrenal axis (HPA) regulation in development and psychopathology. 
These research networks will allow the formation of novel collaborations among
neuroscientists, behavioral scientists, and clinical scientists in order to
develop integrative and cutting edge research project grant applications. It is
increasingly apparent that the HPA system is a leading model for a biological
system that can provide a bridge linking behavior and psychopathology. Moreover,
HPA as it relates to biological and behavioral development, is a prime research
topic for integration across basic and clinical domains. To foster further
integration in this area, NIMH will offer up to $50,000 in direct costs each year
for up to two years, to support travel and meeting costs for each scientific
network. Networks must include representation from multiple perspectives that at
a minimum, span expertise across levels of analysis (e.g., molecular to
behavioral), species (including humans), and disciplines (e.g., behavioral
science, neuroscience, and psychiatry).


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), HPA
Regulation: Cross-Disciplinary Research Networks, is related to the priority
areas of Mental Health and Mental Disorders.  Potential applicants may obtain a
copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/


Applications may be submitted by domestic and for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals, and
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Foreign institutions are not eligible, however, foreign
components may be included in proposed networks applied for by domestic
institutions.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.


This RFA will use the Small Grant (R03) mechanism.  Responsibility for the
planning, direction, and execution of the proposed networks will be solely that
of the applicant.  The total project period for an application submitted in
response to this RFA may not exceed two years.  Although the nature and scope of
the research proposed in response to this RFA may vary, the direct costs
requested each year may not exceed $50,000.

This RFA is one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.

Applicants are strongly encouraged to discuss their applications with program
staff listed under INQUIRIES prior to the submission.


It is estimated that $350,000 (total costs) will be available for the first year
of support for the entire program.  It is anticipated that up to five awards
could be supported by these funds depending on the scientific merit of the
applications received.  Therefore, all funds may or may not be awarded.



The discovery, more the 25 years ago, of corticosteroid receptors (GCR) in the
brain opened important new areas of research on the regulation of many brain-
behavior systems.  A rich literature has been established in the intervening
years on the function of the HPA system, which is the principal biological
substrate regulating glucocorticoid secretion. Many brain regions express GCRs,
and glucocorticoids influence many brain systems. However, they seem to be
primarily associated with responses to environmental challenge and the regulation
of circadian functions.  Interestingly, research with animals has shown that
early manipulations of the HPA system can impair behavioral and neuroendocrine
responses to stress in adults.  These effects are particularly evident when the
early experience involves social impact or trauma.  Similarly, other evidence
demonstrates that the developing brain is very sensitive to glucocorticoid levels
where absence or excessive levels of these steroids can lead to serious effects
on brain structure. Furthermore, individual differences in HPA regulation could
be involved in the development of psychopathology.  For example, higher levels
of cortisol have been associated with temperamental inhibition in children (e.g.,
shyness, fear of novel events).  Temperamental inhibition has been implicated as
a risk factor for the development of childhood internalizing problems, which can
be defined by social withdrawal, anxiety, and depression.  Recent research
suggests that consistently high levels of cortisol may be predictive of later
problems such as anxiety disorder in clinically referred children.  Conversely,
lower cortisol has been associated with other childhood disorders such as
difficulty in regulating anger and attention.  Although some of the mechanisms
of HPA function and glucocorticoid response are known, the ways in which HPA
regulation might be related to the development of various mental disorders is
largely unexplained.  Examination of these and related questions about HPA
regulation are expected to result from interactions within the networks
encouraged by this RFA.


Behavior, psychopathology, the HPA system, and brain responses to glucocorticoids
are each complex issues that have traditionally been studied by investigators in
different disciplines.  To better understand the relationships between these
elements of biology and behavior it may be helpful to form integrated research
programs that span multiple levels of analysis.  This RFA is intended to begin
a process where scientists can overcome barriers to cross-disciplinary research

Scientists interested in the role of HPA regulation in development and
psychopathology may propose the formation of networks of individuals across
disciplinary fields to form collaborative research agendas.  Funds may be
requested to support administrative costs for the Network Director, communication
costs, travel expenses, evaluation and analysis of data by network members in
order to attend and participate in scheduled activities and meetings of the
network.  The purpose of these activities and meetings will be to refine
conceptual frameworks for organizing cross-disciplinary research and identifying
which specific questions and possible experiments show the greatest promise for
advancement.  Moreover, networks are expected to generate creative and well-
designed research plans that address questions that benefit from integrative
perspectives and form the basis of competitive grant proposals.  Investigators
are encouraged not to participate in more than one network, although exceptions
can be made with appropriate scientific justification.  Networks must include
representation from multiple disciplines.  For example, investigators with
expertise in neuroscience, behavioral science, and psychiatry would be highly
appropriate.  Also, networks must span multiple levels of analysis (e.g.,
molecular to behavioral) and are strongly encouraged to include expertise in
animals and humans. Investigators also are encouraged to use networks as an
opportunity to generate pilot data in support of highly focused hypotheses.

Research Themes and Questions

The following is a listing of possible research questions for organizing
networks. It is intended to be used only as a guide in formulating themes that
could be used in developing networks.

Are there systematic individual differences in HPA reactivity, and if so, what
are their implications for behavior and psychopathology?

How is vulnerability determined in the homeostatic processes associated with the
HPA system? And, what determines resiliency and recovery of this system?

How can study of the development of glucocorticoid expression and sensitivity in
animal and primate brain further inform the understanding of development and
psychopathology in humans?

What is the nature (e.g., controllable vs. uncontrollable; physical vs. social
stress) and timing (e.g., perinatal, 6 months, puberty) of environmental events
that affect HPA regulation and development and that pose the greatest risk for

What determines glucocorticoid sensitivity in brain cells, does this vary with
development, and how does this affect behavior and psychopathology?

In addition, networks can be developed to address combinations of questions. 
Examples of such questions include, but are not limited to the following:

What other measures of internal state (e.g., metabolic, physiological) could be
used to compliment measures of HPA regulation and health in humans?

What are the environmental, behavioral, and neuronal mechanisms that down-
regulate the HPA system and how does this regulation affect health?

What interventions (both environmental and biological) can be developed to target
HPA regulation and further test the role of HPA in psychopathology?

How do changes in cognitive abilities associated with human development (e.g.,
cognitive development during puberty) affect HPA regulation?  What animal models
could be used to address these questions?

What is the comparability of the HPA system across species, in terms of
development and pathways of action?

Are there differences between males and females in HPA function, and are
corticolimbic interactions related to HPA function?

What are the mechanisms of the diurnal output of the HPA system, and how does
this relate to neural and behavioral development?

How do changes associated with normal behavioral development correlate with
developmental changes in HPA regulation and accompanying corticolimbic

How does early exposure to increased cortisol (as in the treatment of childhood
asthma) affect HPA regulation and behavior?

What are the regulatory factors controlling glucocorticoid receptor gene


It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.


Prospective applicants are asked to submit, by January 17, 1999, a letter of
intent that includes a descriptive title of the proposed network, the name,
address, and telephone number of the Principal Investigators participating in the
proposed network, 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 a subsequent application, the
information that it contains allows NIMH staff to estimate the potential review
workload and avoid conflict of interest in the review.

The letter of intent is to be sent to:

Della M. Hann, Ph.D.
Division of Mental Disorders, Behavioral Research and AIDS
National Institute of Mental Health
5600 Fishers Lane, Rm 18-105
Rockville, MD  20857
Telephone:  (301) 443-9700
FAX:  (301) 443-6000
Email:  dhann@nih.gov


The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910; telephone (301) 710-0267; fax (301) 480-0525; Email:

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  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, (HPA Regulation: Cross-Disciplinary Research Networks, MH-99-003), must
be typed in section 2 of the face page of the application form and the YES box
must be marked.

The R03 mechanism is limited to ten 10 pages for the substance of the
application.  Appendices including resumes and additional supporting information
may be accepted, although the appendix may not be used to circumvent the page

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

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be sent

Henry J. Haigler, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
5600 Fishers Lane, Room 9C-04
Rockville, MD  20857

Applications must be received by February 17, 1999.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
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 already reviewed, but such applications must include an introduction
addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness by NIMH staff.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  An appropriate peer
review group convened by the NIMH in accordance with the review criteria stated
below will evaluate applications that are complete and responsive to the RFA for
scientific and technical merit.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory Mental Health Council.

Review Criteria

o  Scientific, technical, or medical significance and originality of the
conceptual framework for the proposed network.

o  Appropriateness and adequacy of the network design and membership to carry out
cross-disciplinary discussion.

o  Qualifications and research experience of the Principal Investigator and
network members.

o  Feasibility of network participants successfully completing scheduled meetings
and activities.

o  Appropriateness of the proposed budget and duration in relation to the
proposed network goals.

o  Adequacy of plans to include both genders and minorities and their subgroups
as appropriate for the scientific goals of the network.  Plans for the
recruitment and retention of subjects will also be evaluated.

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.


Scientific merit as determined by peer review and programmatic priorities will
be the primary criteria for award determination. Only applications judged to have
met the highest scientific standards of excellence will be considered for award. 
Networks must demonstrate feasibility for integrated discussions among
investigators in pursuit of cross-disciplinary research agendas.  Networks
proposing themes, which address high-risk experimental questions, but high
potential benefits, will be given careful consideration.


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:

Della M. Hann, Ph.D.
Division of Mental Disorders, Behavioral Research, and AIDS
5600 Fishers Lane, Rm 18-105
Rockville, MD  20857
Telephone:  (301) 443-9700
FAX:  (301) 443-6000
Email:  dhann@nih.gov

Israel Lederhendler, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Rm 11C-16
Rockville, MD  20857
Telephone:  (301) 443-1576
FAX:  (301) 443-4822
Email:  ilu@helix.nih.gov

Douglas L. Meinecke, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Rm 11C-06
Rockville, MD  20857
Telephone:  (301) 443-5288
FAX:  (301) 443-4822
Email:  dmein@helix.nih.gov

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov


This program is described in the Catalog of Federal Domestic Assistance No.
93.242.  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. 
Awards will be administered under PHS grants policy as stated in the NIH Grants
Policy Statement (October 1, 1998).

PHS strongly encourages all grant and contract recipients to provide a smoke-free
workplace and promote the nonuse of all tobacco products.  In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

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