NEUROBIOLOGY AND GENETICS OF FRAGILE X SYNDROME

Release Date:  April 6, 2000

RFA:  HD-00-015

National Institute of Child Health and Human Development
(http://www.nichd.nih.gov) 
National Institute of Mental Health (http://www.nimh.nih.gov) 

Letter of Intent Receipt Date:  June 1, 2000
Application Receipt Date:       July 17, 2000

THIS RFA USES THE “MODULAR GRANT” AND “JUST-IN-TIME” CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE 

The National Institute of Child Health and Human Development (NICHD), through 
its Mental Retardation and Developmental Disabilities (MRDD) Branch, and the 
National Institute of Mental Health (NIMH), in collaboration with the FRAXA 
Research Foundation, invite investigators to submit new, innovative research 
grant applications addressing the epidemiology, genetics, and neurobiology of 
Fragile X syndrome.

This initiative was developed primarily in response to the 1998 NICHD-
sponsored “Workshop on Fragile X:  Future Research Directions.”  Although 
considerable progress has been made recently in several areas of research on 
Fragile X syndrome, there was consensus among workshop participants that 
further progress in those and other areas is now needed.  Fragile X syndrome, 
one of the most common causes of mental retardation and neuropsychiatric disease 
in humans, occurs as a result of the production of “fragile sites” by 
trinucleotide repeat expansion of at least one gene located on the X chromosome.  
While several genes affected by the expansion have been identified, the 
prevalence, risk factors, and nature of the high allele repeats, as well as 
the mechanism and timing of repeat amplifications in various populations, 
need further study.  Mechanisms by which the expression of these genes is 
dysregulated, e.g., by methylation and acetylation, need further study.  
Proteins whose function is altered by interaction with the products of these 
genes need to be identified and the nature of the interaction further 
clarified.  Further correlation of the degree of expansion and expression of 
clinical manifestations of the Fragile X phenotype, particularly behavioral 
manifestations such as autism, autism spectrum disorders, attention deficit 
hyperactivity disorder (ADHD), and anxiety disorders, is needed.  
Experimental systems in model organisms to enable the study of neurobiologic, 
neuroendocrinologic, and reproductive system alterations need to be developed 
and/or studied further at the organismal, cellular, and molecular level at 
various developmental stages.  

The purpose of this RFA is to stimulate research designed to increase our 
knowledge base relevant to Fragile X syndrome in these and other research 
areas by encouraging applications that include, but are not limited to, 
developmental neurobiology, pathophysiology, genetics, proteomics, 
epidemiology, structure-function correlations, and clinical studies that have 
a direct link to Fragile X syndrome. 

HEALTHY PEOPLE 2010

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 RFA, Neurobiology and 
Genetics of Fragile X Syndrome, is related to one or more of the priority 
areas.  Potential applicants may obtain “Healthy People 2010” at 
http://www.health.gov/healthypeople. 

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.  Foreign institutions and organizations 
may apply for an R01 grant, but are not eligible to apply for a small grant 
(R03).  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) Research Project 
Grant (R01) and the NICHD and NIMH Small Grant (R03) award mechanisms.  
Information and application instructions for the NICHD Small Grant are 
available in the NIH Guide for Grants and Contracts at: 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html.  Information and 
application instructions for the NIMH Small Grant are available in the NIH 
Guide for Grants and Contracts at 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html.  Responsibility 
for the planning, direction, and execution of the proposed project will be 
solely that of the applicant.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and will be reviewed according to 
customary NIH peer-review procedures.  Awards resulting from this solicitation 
will be made and administered by either NICHD or NIMH, as appropriate to the 
research focus of the application.  The anticipated date of award is 
April 1, 2001.

Specific application instructions have been modified to reflect “MODULAR 
GRANT” and “JUST-IN-TIME” streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm. 

FUNDS AVAILABLE

The NICHD intends to commit approximately $1 million, the NIMH $200,000, and 
the FRAXA Research Foundation $200,000 in total costs [direct plus facilities 
and administrative (F&A) costs] in FY 2001 to fund six to eight new grants in 
response to this RFA.  An applicant for an R01 grant may request a project 
period of up to five years and a budget for direct costs of up to $200,000 
per year.  An applicant for an R03 grant may request a project period of up 
to two years and a budget for direct costs of $50,000 per year.  Because the 
nature and scope of the research proposed may vary, it is anticipated that 
the size of R01 awards also will vary.  Although the financial plans of 
NICHD, NIMH, and the FRAXA Research Foundation provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds for this purpose and the receipt of a sufficient number of meritorious 
applications.

RESEARCH OBJECTIVES

Background

Fragile X syndrome, one of the most common causes of inherited mental 
retardation and neuropsychiatric disease in human beings, affects as many as 
one in 2000 males and one in 4000 females.  Trinucleotide repeat expansion of 
at least three genes located on the X chromosome has been associated with the 
formation of “fragile sites.”  Trinucleotide expansions within two of these 
genes, FRAXA (within the FMR1 gene) and FRAXE (within the FMR2 gene), are 
associated with mental retardation, while that at a third, FRAXF (not yet 
associated with a specific gene) is not.  Mutations in the FMR1 gene, for 
example, produce expansion of CGG repeats in the 5’ untranslated region of 
the gene and lead to a severely disabling neurodevelopmental disorder.  Such 
expansion leads to physical, neurocognitive, and emotional characteristics 
linked to, but not exclusively determined by, alterations in the FMR1 gene or 
the level of its protein, FMRP.  While such expansions can be detected in all 
races and ethnic groups, epidemiological studies to assess prevalence, risk 
factors, and the nature of the high allele repeats are needed; populations 
may not be equivalent with respect to the Fragile X expansion.  The mechanism 
and timing of repeat amplifications in various populations, similarly, are 
not known.  

Approximately 15-25 percent of individuals with Fragile X syndrome also are 
diagnosed with mild to moderate autism and autism spectrum disorders.  FMRP 
expression and autistic status appear to be associated with developmental 
outcome.  Other clinical abnormalities include attention deficit 
hyperactivity disorder (ADHD) and anxiety disorders.

Current methods for prenatal diagnosis of gene expansion of FRAXA, associated 
with FMR1 and its encoded protein, FMRP, are accurate, sensitive, and 
relatively inexpensive.  For such methods to be applied as general screening 
techniques, more knowledge about prevalence, risk factors, and nature of high 
repeat alleles needs to be obtained.  Because populations may not be 
equivalent with respect to Fragile X expansion, consideration of ethical 
issues related to variability of phenotype, the possibility of mislabeling, 
and the value of screening if there is no definitive therapy, is required.

Although FMR1 is subject to X inactivation, abnormal methylation appears to 
contribute to the phenotype observed in mosaic patients.  These individuals 
experience upregulation of the FMR1 gene.  Further, expanded repeats appear 
to be abnormally methylated from the start, although the mechanism by which 
such abnormal methylation occurs remains unknown.  Expanded FMR1 genes are 
also “silenced” through a process of deacetylation.  Studies focusing on 
alteration of both of these processes are needed. 

FMRP is found in both nucleus and cytoplasm, where it binds with mRNAs 
associated with ribonucleoproteins (RNPs) specifically associated with 
polyribosomes.  FMRP-associated RNPs are located in the cell body, as well as 
in the dendrites, at the base of dendritic spines.  Thus, FMRP may play a 
role in synaptic function and plasticity.  Studies to determine the specific 
RNAs bound by FMRP, particularly those to which the expanded FMRP binds, are 
needed to identify how FMRP modulates translation of interacting messages, 
and whether the messages modulated differ in cell body and dendrite. 

Individuals with Fragile X syndrome also exhibit neuroendocrinological and 
reproductive disorders.  Macroorchidism occurs in males with overt Fragile X 
syndrome.  Premature ovarian failure occurs in females who do not have the 
number of CGG repeats to produce overt Fragile X syndrome, but have an 
expanded number of repeats with few or no apparent neurological symptoms 
(premutation carriers).  Structural, neurochemical, and hormonal 
abnormalities, therefore, need to be put together with a specific 
pathophysiological or neurodevelopmental mechanism.

Variation in the cognitive and behavioral phenotype of the Fragile X syndrome 
has been demonstrated in intellectual functioning, learning disability, 
executive function, attention, hyperactivity, depression, anxiety, and 
autistic behaviors.  The explanation for this variation in phenotypic 
expression may depend on understanding the role of genetics and brain 
development in cognition and behavior.  Therefore, further studies are needed 
correlating the clinical manifestations of the Fragile X phenotype with the 
neurodevelopmental processes that underlie the Fragile X syndrome.  This will 
lead, in turn, to a model of neurodevelopmental variation in specific 
cognitive and behavioral dysfunction.

For treatment modalities to be instituted, suppression of expansion, 
restoration of expression, small molecule agents, and gene replacement need 
to be considered.  Animal models are necessary for the evaluation of 
therapeutic strategies.  For animal models to be effective, definition of the 
animal phenotype is only as good as the characterization of the human 
phenotype.  The human phenotype includes deficits in executive function and 
social-behavioral problems.  Sensitivity to stimuli needs to be determined.  

Research Scope

This RFA focuses on neurobiological and epidemiological studies relevant to 
understanding the genetic and pathophysiologic basis of Fragile X syndrome.  
Examples of the types of studies addressing Fragile X syndrome that may be 
proposed in response to this RFA include, but are not limited to, the 
following: 

o  Development of methods to better refine the definition of the clinical 
phenotype of Fragile X syndrome, focusing on its characteristic component 
behavioral and cognitive features. 

o  Environmental studies including the influence of culture and ethnicity as 
variables in developing a better understanding of the correlation between 
genotype-phenotype and patient outcome. 

o  Neurodevelopmental and longitudinal studies to characterize the 
neuropathological progression and inherent variability in Fragile X patients 
in order to develop specific hypotheses about the initial (primary) 
abnormality, and to address the degree to which phenotypic variation relates 
to postnatal brain development.

o  Histological, neurochemical, brain-imaging, and structure-function studies 
to define the molecular, cellular, and/or biochemical basis of this disorder 
and facilitate development of specific hypotheses about the basic 
abnormalities involved in Fragile X syndrome.  

o  Studies examining the mechanism by which Fragile X genetic status affects 
the development, function, and dysfunction of the nervous system, 
particularly with respect to cognition and behavior.

o  Studies applying imaging, electrophysiology, pharmacology, molecular 
biology, and behavioral science techniques to follow the developmental 
trajectories of different brain functions onto developing cognitive and motor 
skills.

Animal models are important resources for studying pathology and therapeutic 
strategies.  Although some animal models have been created, there is still 
need for models for behavioral screening as well as therapeutic interventions 
that include suppression of expansions and restoration of expression.  
Specifically, topics that may be addressed include, but are not limited to:

o  Creation of conditional tissue-specific targeted knock-out animal models.

o  Development and use of animal models that have specific relevance to 
Fragile X based on clear neurodevelopmental, pathophysiological, genetic, 
and/or functional homology.

o  Development and use of animal models to test existing medications and 
develop new psychopharmacologic medications that are safe and effective for 
Fragile X patients.

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 are 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,” published in the Federal Register of March 28, 1994 (FR 59 14508-
14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, 
March 18, 1994, and available on the Internet at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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/or 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 Inclusion of Children as Participants in 
Research Involving Human Subjects,” published in the NIH Guide for Grants and 
Contracts, March 6, 1998, and available at: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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

LETTER OF INTENT

Prospective applicants are asked to submit 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 this RFA.  
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 allows NICHD staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent to Dr. Mary Lou Oster-Granite at the 
address listed under INQUIRIES, below, by June 1, 2000.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

APPLICATION PROCEDURES

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, on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-435-0714, E-mail:  grantsinfo@nih.gov.

Application Instructions for NICHD Small Grant (R03) Applications

The small grant (R03) research mechanism should be used for support of pilot 
studies and/or exploration of novel hypotheses and strategies that are sound 
and justifiable, but not sufficiently developed for the R01 mechanism.  A 
description of the NICHD Small Grants Program and complete application 
instructions are available from the program contact listed under INQUIRIES 
and on the Internet at 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html.  These 
applications must be submitted according to the Modular Grant application 
instructions included in the NICHD Small Grant program announcement.

Application Instructions for NIMH Small Grant (R03) Applications

The NIMH Small Grants Program provides research support in areas of high 
relevance to the mission of the NIMH.  Small grants are short-term awards 
designed to answer specific and targeted research questions.  Both new and 
more experienced investigators are encouraged to apply for grants under this 
announcement.  Newer investigators may use the award to generate new or 
additional preliminary data for future research grants (e.g., R01).  Priority 
will be given to applications in any of the following four categories:  1.  
Newer, less experienced investigators.  2.  Investigators at institutions 
without well-developed research traditions and resources.  3.  More 
experienced investigators, for exploratory studies that represent significant 
change in research direction for them.  4.  More experienced investigators, 
for developing and testing new methods or techniques.  A description of the 
NIMH Small Grants Program and complete application instructions are available 
from the program contact listed under INQUIRIES and on the Internet at 
http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html.  These 
applications must be submitted according to the Modular Grant application 
instructions included in the NIMH Small Grant program announcement.

Modular Grant Application Instructions for Research Project Grant (R01) 
Applications

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers, and NIH 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $200,000 per year. The total direct costs 
must be requested in accordance with the program guidelines and the 
modifications made to the standard PHS 398 application instructions described 
below:
o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete Form Page 
4 of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget Narrative 
page.  (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.)  At the top of the page, enter the Total Direct Costs 
requested for each year.  This is not a Form Page.

Under Personnel, list key project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of Total Costs (Direct 
plus F & A) for each year, each rounded to the nearest $1,000.  List the 
individuals/organizations with whom consortium or contractual arrangements 
have been made, the percent effort of key personnel, and the role on the 
project.  Indicate whether the collaborating institution is foreign or 
domestic.  The total cost for a consortium/contractual arrangement is 
included in the overall requested modular direct cost amount.  Include the 
Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the Form Page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST:  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

o  The applicant should provide the name and telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.

Submission Instructions

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number HD-00-015.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note this 
is in the pdf format.  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 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: 

CENTER FOR SCIENTIFIC REVIEW 
NATIONAL INSTITUTES OF HEALTH
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 should be 
sent to:

L. R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03, MSC 7510
Bethesda MD 20892-7510
Rockville MD 20852 (for express/courier service)

Applications must be received by July 17, 2000.  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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness to this RFA by NICHD and NIMH.  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 NICHD in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will receive a written 
critique and may 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 Child 
Health and Human Development Council and/or the National Advisory Mental 
Health Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out an important work that is 
by its nature not innovative, but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches, or 
methods?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

In addition to the above criteria, in accordance with NIH policy, all 
applications also will be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects also will be 
evaluated.

o  The reasonableness of the proposed budget and its duration in relation to 
the proposed research. 

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent that they may be adversely affected by the project 
proposed in the application.

SCHEDULE

Letter of Intent Receipt Date:    June 1, 2000
Application Receipt Date:         July 17, 2000
Peer Review Date:                 October 2000
Council Review:                   January 2001
Earliest Anticipated Start Date:  April 1, 2001

AWARD CRITERIA

The following factors will be considered in making award decisions:  
Scientific merit of the proposed project as determined by peer review; 
availability of funds; and program priority.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.  Applicants may 
also consult with NIH staff for advice about collaborations and access to 
patients and patient material. 

Direct inquiries regarding programmatic issues to:

Mary Lou Oster-Granite, Ph.D.
Mental Retardation and Developmental Disabilities Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B-09, MSC 7510	
Bethesda, MD 20892-7510
Telephone: (301) 435-6866
FAX: (301) 496-3791
E-mail: mo96o@nih.gov

Steven O. Moldin, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Blvd., Room 7189, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-2037
FAX: (301) 443-9890
E-mail:  smoldin@mail.nih.gov 

Direct inquiries regarding fiscal matters to:

Mr. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A-17, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 435-6999
FAX: (301) 402-0915
E-mail:  es65o@nih.gov

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd., Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX: (301) 443-6885
E-mail:  Diana_Trunnell@nih.gov 

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.865, (NICHD) and 93.242 (NIMH).  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act, as amended (42 USC 241 
and 284) and administered under NIH grants policies and Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-use 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 portions 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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