Full Text MH-97-003
 
MOLECULAR APPROACHES TO MENTAL DISORDERS OF LATE LIFE
 
NIH GUIDE, Volume 26, Number 13, April 25, 1997
 
RFA: MH-97-003
 
P.T. 34

Keywords: 
  Mental Disorders 
  Neuroscience 
  Psychopathology 

 
National Institute of Mental Health
 
Letter of Intent Receipt Date: June 5, 1997
Application Receipt Date: July 10, 1997
 
PURPOSE
 
The principal objective of this Request for Applications (RFA) is to
attract new investigators to build upon and extend basic research on
fundamental aspects of neuronal function to develop clinical
approaches to the understanding of mechanisms, clinical course, and
treatment of late life mental disorders. The results of these
investigations are expected to lead to the development of novel
therapeutic strategies that reduce symptoms of psychopathology and
improve neurobehavioral functioning in late life.  The major focus of
this RFA is on late onset mental disorders: psychoses, affective
disorders, and anxiety disorders.
 
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), Molecular Approaches to Mental Disorders of
Late Life, is related to the priority area of mental health and
mental disorders. Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary
Report: Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic 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.  Foreign institutions
are not eligible for these awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) First
Independent Research Support and Transition (FIRST) (R29) award and
the small grant program (R03) award. The anticipated award date is
September 30, 1997. Investigators seeking support for topics relevant
to this RFA through other mechanisms such as career development
awards (K series) or other research grant mechanisms (R01, R10, etc.)
are encouraged to submit investigator-initiated applications using
regular NIH procedures.
 
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.
Because the small grants and FIRST awards have special eligibility
requirements, application formats, and review criteria, applicants
are strongly encouraged to consult with program staff listed under
INQUIRIES and obtain the appropriate guidelines for these grant
mechanisms.
 
FUNDS AVAILABLE
 
It is estimated that $750,000 (total costs) is available for support
of up to 10 new awards.
 
RESEARCH OBJECTIVES
 
Background
 
Dramatic advances have taken place in our understanding of the basic
cellular and molecular biology of neuron function. Four areas of
investigation have produced results that hold exceptional promise for
application to the treatment of mental disorders of late life. These
areas include: the molecular basis of signal transduction and its
relation to neural plasticity and long term adaptation; neurotrophic
growth factors and their effects on neural function and pathology;
the mechanisms of programmed cell death in the aging brain; and the
functional impact of cell death, growth factors, and signal
transduction on patterns of neural connectivity and function. This
RFA is intended to promote and facilitate the translation of these
basic research findings into clinically applicable technologies.
Major goals will be the elucidation of fundamental mechanisms of late
life mental disorders with the intention of immediate or near-term
development of novel therapeutic approaches. Clinical applications
include depression, psychosis, and anxiety disorders of late life.
 
As the molecular events associated with signal transduction are known
in greater detail, it is increasingly appreciated that interactions
between signaling molecules are a major determinant of how neurons
respond to stimuli. Following activation of a receptor by its ligand,
a cascade of biochemical events takes place. Changes in signal
transduction systems are believed to form the basis for many
phenomena associated with neural plasticity and adaptation to chronic
stimuli. Thus chronic exposure to psychotropic drugs may lead to
alterations in expression of G proteins, protein kinases, and many
other signal transduction-associated molecules that alter the way
neurons respond to synaptic transmitters. These chronic changes lead,
in turn, to alterations in behavior, thought process, and affect.
There is growing evidence that aging itself produces changes in
signal transduction systems that alter neuronal function. The
investigation of age-associated changes in signal transduction may
lead to significant advances in our understanding of the mechanisms
of mental disorders of late life and to the development of new
treatment approaches.
 
Molecular signaling processes often converge, overlap, and influence
each other at many levels from receptors to transcription factors.
Thus, a cell is constantly integrating signals from multiple
neurotransmitters, growth factors, matrix and adhesion molecules, and
hormones. This "crosstalk" between signaling systems may explain a
wide variety of neurobiological phenomena ranging from LTP to
cross-tolerance among addicting drugs. Crosstalk may also account for
interactions that occur when combinations of psychotropic drugs are
used to treat patients who have complex affective and psychotic
symptoms or when augmentation strategies are employed to treat
patients who are refractory to single agents. The aging process may
produce alterations in patterns of crosstalk between signaling
systems that result in significant functional changes in neurons.
Interactions between growth factor-related signaling and
neurotransmitter-associated systems is of special interest in
understanding the effects of aging on central nervous system
function.
 
A major opportunity exists for the application of refined
understanding of signal transduction mechanisms to the development of
pharmacotherapeutics for late life mental disorders. In particular,
the study of the effects of aging on signal transduction processes
and neuronal plasticity will lead to new understanding of drug
mechanisms and to the development of novel therapeutic strategies for
mental disorders of late life. In addition, new augmentation
strategies and drug combination protocols may be developed that
exploit interactions between signaling systems. Moreover, signaling
systems that are difficult to target with conventional
pharmacotherapeutic agents such as growth factor or neuropeptide
receptors may be influenced indirectly by activating or inhibiting
distinct signaling pathways.
 
Our knowledge of the mechanisms underlying destruction and
degeneration of cell groups in the brain is rapidly advancing.
Currently, there is substantial evidence that programmed cell death
is a major mechanism underlying many neurodegenerative processes in
the nervous system. Programmed cell death utilizes mechanisms and
pathways that are common to many forms of injury including trauma,
ischemia, infectious agents, and the aging processes. Neuronal cell
death in specific brain regions is believed to be associated with the
development of neuropsychiatric symptoms in late life. For example,
degenerative changes of subcortical nuclei including the nucleus
basalis of Meynert, the substantia nigra, the locus coeruleus, and
the dorsal raphe may be associated with disorders of cognition,
thought, affect, and anxiety in the elderly. In addition to neuronal
cell death, mental disorders of aging may reflect dysregulation of
growth factor activity leading to atrophic or dystrophic changes in
neuron structure and function.
 
Because of their role in preventing cell death, neurotrophic growth
factors have been the subject of intense research as therapeutic
agents in the treatment of neurodegenerative disorders such as
Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral
Sclerosis. In addition to blocking programmed cell death,
neurotrophic growth factors are among the most potent modifiers of
neuronal function known. Growth factors alter electrochemical
activity, neurotransmitter synthesis and release, axonal transport,
signal transduction, gene transcription, and cellular structure.
Because of these properties, neurotrophic growth factors may be
useful in the treatment of other mental disorders of aging that are
believed to involve either atrophic or dystrophic changes in neurons.
These disorders include late-onset psychoses, affective disorders,
and anxiety disorders. Lastly, neurotrophic growth factors play a
protective role in ischemic injury produced by stroke and
microvascular disease. This suggests that growth factors may be
useful in the treatment of vascular dementias, post-stroke
depression, and other late life mental disorders associated with
vascular insufficiency.
 
In addition to growth factors, small molecules that influence growth
factor signaling and apoptosis-related biochemical events are
currently being developed and investigated. However, to facilitate
this process, more research is needed into the basic mechanisms of
cell death and growth factor action. In addition, research is needed
to develop wider applications of neurotrophic and anti-apoptotic
therapeutic strategies to diseases of the central nervous system.
Neurotrophic growth factors and other drugs that exert trophic
effects on neurons present an exceptional opportunity for
investigation as novel therapeutic agents for mental disorders of
late life. A central goal of this RFA is to stimulate the
investigation of the mechanisms of action of neurotrophic growth
factors and to explore potential therapeutic applications of growth
factors and related agents to neuropsychiatric disorders of aging.
Major opportunities for advancing the field exist in each of the
following areas: 1) elucidation of basic biochemical mechanisms of
programmed cell death and neurotrophic growth factor action; 2)
application of growth factors to the treatment of neuropsychiatric
disorders (including development of novel strategies for CNS
delivery); 3) development of small molecules the mimic the effects of
growth factors or modulate growth factor signaling; 4) exploration of
other novel anti-apoptotic therapeutic agents.
 
Neural cell death, atrophy, and other age-related changes profoundly
alter patterns of connectivity and neural circuitry in the aging
brain. In addition, neurotrophic growth factors have recently been
shown to significantly influence connectivity. Moreover, biochemical
changes in signal transduction mechanisms influence the functional
and electrophysiological properties of neural circuits. Therefore, a
pivotal step in the translation of molecular research into behavioral
and clinical application is the investigation of neural connectivity
in the aging brain. Rapid advances are being made in the study of
neural circuitry and its relationship to behavior. A major area to be
supported by this RFA focuses on investigation of molecular processes
of aging at the level of neural connectivity emphasizing its
implications for behavior and therapeutics.
 
Research Issues
 
Broad research objectives appropriate to this RFA include (but are
not limited to) the following:
 
Identification of changes in signal transduction systems that occur
in normal aging and disease states
 
Elucidation of the molecular mechanisms of enhanced receptor
sensitivity following chronic dopaminergic receptor blockade
 
Evaluation of the chronic effects of drug treatment and stress on
signaling proteins in the aging brain
 
Anatomical and electrophysiological studies of the effects of growth
factors and chronic drug treatment on neural circuitry and behavior
in the aging brain
 
Investigation of interactions between signaling systems (e.g. growth
factor-induced kinase activity that modulates
neurotransmitter-associated signaling cascades)in the aging brain
 
Investigation of changes in expression of neurotrophic growth
factors, cytokines, growth factor-associated receptors and signaling
molecules in the aging brain
 
Identification of novel neurotrophic factors and cytokines expressed
in the aging brain
 
Investigation of the physiological role of growth factors and
cytokines in the adult brain
 
Investigation of non-neurotrophic effects of growth factors on
neuronal functioning
 
Elucidation of basic mechanisms of programmed cell death in the aging
brain as it may relate to late life mental disorders
 
Development and application of small molecules that influence
(activate or inhibit) growth factor-related signaling and apoptotic
cell death mechanisms such as tyrosine phosphatase inhibitors, ICE
inhibitors, bcl-2-like molecules etc.
 
Development of technology to improve delivery of growth factors and
other large molecular ligands across the blood brain barrier
 
Studies of neurobehavioral effects of neurotrophic growth factors and
cytokines in the aging brain
 
Application of antisense technology to modulate expression of key
signaling, neurotrophin-related, or apoptosis-associated gene to
determine effects of such procedures on behavior
 
Development of clinical imaging technology to assess signal
transduction systems in the aging brain
 
Development of clinical pharmacological challenge protocols that
assess signal transduction and trophic states in the aging brain
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by June 5, 1997, 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 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:
 
Herbert W. Harris, M.D., Ph.D.
Division of Clinical and Treatment Research
National Institute of Mental Health
Parklawn Building, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-1185
FAX:  (301) 574-6784
E-mail: hharris@ngmsmtp.nimh.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Extramural Outreach and Information Resources, National Institutes of
Health,  6701 Rockledge Drive,  MSC 7910, Bethesda, MD 20892-7910;
telephone (301) 435-0714; fax (301) 480-0525; Email:
ASKNIH@ODROCKM1.OD.NIH.GOV.
 
Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
The RFA label available in the PHS 398 (rev. 5/95) 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, MH-97-003,
Molecular Approaches to Mental Disorders of Late Life, must be typed
in section 2 of the face page of the application form and the YES box
must be marked.
 
Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)
 
At the time of submission, two additional copies of the application
must be sent to:
 
Henry J. Haigler, Sr., Ph.D.
Division of Extramural Activities
National Institute of Mental Health
Parklawn Building, Room 9C-08
Rockville, MD  20857
Telephone:  (301) 443-1340
Fax:  (301) 594-0702
Email: hhaigler@nih.gov
 
Applications must be received by July 10, 1997.  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 RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  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 already reviewed, but such applications must include an
introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIMH
staff.  Incomplete and/or non-responsive applications will be
returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIMH in accordance with the review
criteria stated below.  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 appropriate national advisory council or
board, when applicable.
 
Review Criteria
 
o  ability of investigators to engage a multi disciplinary research
program spanning basic to clinical research with the endpoint of
enhancing our understanding of mental disorders of late life
 
o  Focus of the investigation on the specific mental disorders of
aging which include: major mood disorders, anxiety disorders,
psychotic (thought) disorders with a lesser focus on Alzheimer's
disease
 
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 the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
AWARD CRITERIA
 
Award criteria are:  scientific merit as determined by peer review,
availability of funds, and programmatic priorities.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Herbert W. Harris, M.D., Ph.D.
Mental Disorders of the Aging Research Branch
Division of Clinical and Treatment Research
National Institute of Mental Health
Parklawn Building, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-1185
FAX:  (301) 574-6784
E-mail hharris@helix.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Diana S. Trunnell
Assistant Chief, Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov
 
AUTHORITY AND REGULATIONS
 
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 Public Health Service Grants Policy Statement (April 1, 1994).
 
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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