FRAGILE X RESEARCH CENTERS

Release Date:  January 3, 2002

RFA:  RFA-HD-02-009

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

Letter of Intent Receipt Date:  June 23, 2002
Application Receipt Date:       July 23, 2002

PURPOSE

The National Institute of Child Health and Human Development (NICHD), through 
its Mental Retardation and Developmental Disabilities (MRDD) Branch, invites 
investigators to submit grant applications to establish Fragile X Research 
Centers, affiliated with an existing NICHD Mental Retardation and 
Developmental Disabilities Research Center (MRDDRC), to conduct research to 
improve the diagnosis and treatment of, and to find a cure for, Fragile X 
syndrome.

This initiative was developed primarily in response to the Children"s Health 
Act of 2000 (H. R. 4365) Section 452E, which directs that the "…Director of 
the Institute, after consultation with the advisory council for the 
Institute, shall expand, intensify and coordinate the activities of the 
Institute with respect to research on the disease known as fragile X.  …The 
Director shall, to the extent that amounts are appropriated…provide for the 
establishment of at least three fragile X research centers…only if the grant 
or contract has been recommended after technical and scientific peer review 
required by regulations under section 492…The Director of the Institute, with 
the assistance of centers established…shall conduct and support basic and 
biomedical research into the detection and treatment of fragile X.  The 
Director of the Institute shall, as appropriate, provide for the coordination 
of the activities of the centers assisted...including providing for the 
exchange of information among the centers.  Each center…shall use the 
facilities of one institution, or be formed from a consortium of cooperating 
institutions, meeting such requirements as may be prescribed by the Director 
of the Institute.  Support may be provided for a center…for a period not 
exceeding 5 years.  Such period may be extended for one or more additional 
periods, each of which may not exceed 5 years, if the operations of such 
center have been reviewed by an appropriate technical and scientific peer 
review group established by the Director and if such group has recommended to 
the Director that such period be extended…" 

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 several genes 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, also 
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 establish Fragile X Research Centers affiliated 
with existing MRDDRCs 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 need not be limited to, 
developmental neurobiology, pathophysiology, genetics, proteomics, 
epidemiology, structure-function correlations, and clinical, behavioral and 
biobehavioral studies directly relevant to Fragile X syndrome. 

These Fragile X Research Centers are intended to serve as a national 
resource.  They should form networks that foster communication, innovation, 
and high-quality research in Fragile X syndrome.  They also should provide a 
stimulating, multidisciplinary environment that attracts both established and 
promising new investigators.  

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas. This RFA 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 for-profit and non-profit 
organizations, public and private, that currently have an MRDDRC P30 grant.  
The application may include components of the Fragile X Research Center that 
are located at the existing MRDDRC and/or at affiliated domestic or foreign 
sites.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to participate in the application for a Fragile X 
Center.

Scientific personnel and institutional resources capable of providing a 
strong research base in Fragile X must be available for an existing MRDDRC to 
meet the requirements of this RFA.  A strong institutional commitment at each 
institution involved also must be demonstrated.  The commitment may take the 
form of faculty appointments for investigators, purchase of research 
equipment, or assignment of research space to facilitate collaborative 
research and interdisciplinary interaction.  Affiliation with and utilization 
of at least one Core within an existing MRDDRC is required for a Fragile X 
Research Center application to be responsive to this RFA.

For further information regarding the application, contact the Program Staff 
listed under INQUIRIES.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Center Core Grant 
(P30) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed projects will be solely that of the applicant.  The 
application is to be submitted as a P30 supplement by the Principal 
Investigator of the MRDDRC, in collaboration with the person designated to be 
the Director of the Fragile X Research Center, who also shall serve as the 
Associate Director of the MRDDRC for Fragile X Research.  The Principal 
Investigator of the MRDDRC may also serve as the Director of the Fragile X 
Research Center. 

The supplement within a P30 Center is designed to encourage and support 
broadly based multidisciplinary research programs that have a well-defined 
central research focus or objective in Fragile X syndrome research.  This 
supplement, the Fragile X Research Center, is based on a unique and new 
concept for the purposes of this RFA:  a "Center within a Center."  Because 
the concept is unusual, careful attention must be paid by applicants to the 
requirements contained in this RFA.  Applications failing to adhere to these 
instructions will be returned to the applicant without review.   

An important feature of this new "Center within a Center" concept is that the 
interrelationships among the individual projects and Cores proposed for the 
Fragile X Research Center will result in a greater contribution to the 
overall MRDDRC goals than if each project was pursued independently.  The 
application requires a minimum of three related, integrated, and high-quality 
research projects that provide a multi-disciplinary, yet unified, approach to 
the problems being investigated by the Fragile X Research Center.  The 
application may request support for certain common core resources, including 
core services provided by the existing MRDDRC.  

FUNDS AVAILABLE

The NICHD intends to commit approximately $3.375 million in total costs 
[Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund 
at least three Fragile X Research Centers as supplemental "Center within a 
Center" components of existing MRDDRC P30 Centers in response to this RFA.  
An applicant for a Fragile X Research Center grant may request a project 
period of up to five years and a budget for total costs of up to $1.125 
million in the first year.  However, NIH policy limits duration of 
competitive supplements to the time remaining on the parent grant, so formal 
budget requests in the application will have limitations.  Prospective 
applicants should contact NICHD staff listed under INQUIRIES, below, for 
directions in preparing applications to deal with this situation.  Although 
the financial plans of NICHD provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds 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 degree or type of 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 associated with Fragile X syndrome 
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.  In neurons, 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 the cell 
body and dendrite. 

Individuals with Fragile X syndrome also exhibit neuroendocrinologic 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 internal and environmental 
stimuli, particularly sensory stimuli, needs to be determined.  

Research Scope

This RFA is designed to create Fragile X Research Centers whose participating 
investigators would direct research efforts toward neurobiological, 
behavioral, biobehavioral, and epidemiological studies relevant to 
understanding the genetic and pathophysiologic basis of Fragile X syndrome, 
studies that may lead to the development of novel or adapted treatment 
strategies.  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 and their influence on 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. 

Research Projects

Research proposed for inclusion in the Fragile X Research Center must 
represent new research projects.  Projects relevant to Fragile X syndrome 
research that are currently supported by the R01, P01 or other funding 
mechanisms may not apply for "supplemental" funds that extend or modify their 
scope under this RFA.  Projects that represent competing continuations of 
existing R01 and P01 project components, however, are eligible to be 
incorporated into a Fragile X Research Center application as "new" research 
projects, provided that they withdraw any overlapping applications currently 
funded or under review.  The budgets of individual research projects may not 
exceed $250,000 in total costs per year. 

SPECIAL REQUIREMENTS

Collaborative Arrangements

Two or more institutions that can demonstrate a feasible plan for 
collaborative research may apply to form a Fragile X Research Center.  One of 
these institutions must have an existing MRDDRC.  Evidence of prior 
collaboration and/or a plan for proposed collaborations between the 
investigators and proposed access to at least one Core facility at the 
affiliated MRDDRC should be cited.  An existing MRDDRC may submit only one 
Supplemental "Center within a Center" Fragile X Research Center application.  
Individual Directors of Fragile X Research Center Projects or Cores may 
affiliate with more than one MRDDRC for the purpose of establishing a Fragile 
X Research Center.  However, Research Project Directors must apply for 
support of unique, distinct, and non-overlapping research projects at each 
MRDDRC/Fragile X Research Center with which they affiliate.  Core Directors 
may provide Core services for more than one Fragile X Research Center.  
However, with the exception of the Administrative Core, these Core services 
must not duplicate MRDDRC Core services at the affiliated MRDDRC.  The 
application must provide details of agreements regarding sub-contracting 
arrangements, coordination, and support of activities at and among 
participating institutions, and must demonstrate the potential effectiveness 
of such collaboration for the ongoing work of the Fragile X Research Center.

Center Structure and Requirements 

All applications for a Fragile X Research Center must be submitted through 
and by one of the 14 existing NICHD MRDDRCs, as a request for a Supplement to 
the P30 Center Core grant for the purpose of creating a "Center within a 
Center," the Fragile X Research Center within the existing MRDDRC.  A list of 
these MRDDRCs is available at 
http://www.nichd.nih.gov/RFA/HD-02-009/HD-02-009.htm 
and from the program contact identified under INQUIRIES, below. 

o  The application may consist (a) entirely of research projects and cores 
within the home institution of the MRDDRC, or (b) partly of research projects 
and/or cores from an MRDDRC home institution and partly of projects and cores 
to be located at one or more domestic or foreign institutions that together 
form a collaborative affiliation with the MRDDRC for the purposes of forming 
a Fragile X Research Center.  In the latter case, at least one core proposed 
for use by the Fragile X Research Center must be among the existing Cores of 
the MRDDRC.   Applications must have IACUC approval for all projects or Cores 
that involve the use of vertebrate animals PRIOR to the date of submission of 
the application. 

o  An application for a competitive supplement to an existing grant must be 
submitted by the Principal Investigator of the existing grant as the 
Principal Investigator of the supplement request.  In order to offer maximum 
flexibility and scientific expertise in leadership of the Fragile X Research 
Center, an individual other than the Principal Investigator of the MRDDRC may 
be identified as the Director of the Fragile X Research Center of the MRDDRC.  
An institution other than the parent institution of the MRDDRC may employ 
this individual.  In this instance, the Director of the Fragile X Research 
Center shall be listed as the Co-Principal Investigator for the supplement 
request, and shall also be designated as the Associate Director of the MRDDRC 
for Fragile X Research.

o  It is the intent of the NICHD that the Fragile X Research Center shall be 
an identifiable entity as a "Center within a Center" in the organizational 
structure of the MRDDRC.  Applicants must indicate how they intend to meet 
this requirement.  Applicants must present a plan that identifies clearly how 
the Fragile X Research Center will enhance the affiliated MRDDRC mission, 
increase its diversity, and meet existing requirements for Core access.  
Similarly, the MRDDRC must indicate how each component of the Fragile X 
Research Center will benefit from its affiliation with the MRDDRC.  NICHD 
also expects that the Directors of the Fragile X Research Centers will attend 
the annual meetings of the MRDDRC Directors with NICHD staff.  

Required Application Components

Applications for P30 supplements in response to this RFA must contain 
descriptions of three components:  (1) An Administrative Core unit, directed 
by the Fragile X Research Center Director, (2) at least three independent 
Research Projects, directed by Research Project Leaders, and (3) Support 
Cores, as needed, directed by Support Core Leaders.  These components are 
described below.  For Fragile X Research Centers that extend beyond an 
existing MRDDRC, at least one of the Support Cores to be accessed by Fragile 
X Research Center investigators must be an existing Core at the MRDDRC with 
which the Fragile X Research Center has established an affiliation.  Each 
application must include all components, however, one or more of the 
components may be located at collaborating domestic and/or foreign 
institutions or at the affiliated MRDDRC (see below).

o  Fragile X Research Center Director:  The scientist who is designated by 
the applicant institution to direct the Fragile X Research Center.  Both the 
Principal Investigator of the MRDDRC and the Fragile X Research Center 
Director will assume responsibility and accountability to the applicant 
institution and to the NICHD for the performance and proper conduct of the 
Fragile X Research Center in accordance with the requirements specified in 
this RFA.  The Fragile X Research Center Director is responsible for the 
Administrative Core unit. 

o  Administrative Core:  A separately budgeted administrative unit that 
manages daily operations of the Fragile X Research Center.  The 
Administrative Core unit, under the direction of the Fragile X Research 
Center Director, will coordinate all the operations of the Fragile X Research 
Center.  The Administrative Core will ensure that the aims of the Research 
Projects are carried out by the Research Project Leaders and that Support 
Cores provide the necessary services to further the research aims. 

The Administrative Core may propose to provide salaries and support for a 
limited number of administrative and clerical personnel, such as the Fragile 
X Research Center Director, secretaries, and clerical support staff.  Staff 
will use criteria defined under revised OMB Circular A-21 to determine 
whether direct charging for administrative and clerical staff will be 
allowed.  The Administrative Core, particularly if it is located at an 
institution other than that of the affiliated MRDDRC, may propose 
administrative support services, including supplies, duplication, telephone, 
and maintenance contracts for equipment when not covered by institutional 
Facilities and Administrative charges or by the Administrative Core of the 
affiliated MRDDRC.  Travel by the Director of the Fragile X Research Center 
to meetings of the MRDDRC Directors to discuss scientific advances in the 
Fragile X Research Center should be included in the application.

Other costs that may be proposed by the Administrative Core of the Fragile X 
Research Center include costs related to dissemination of research results to 
the scientific community and lay public and costs of research-related 
seminars or meetings designed to promote interdisciplinary interaction, 
education, or center cohesiveness.  Costs may NOT be requested for salary and 
support of central administrative personnel usually paid from institutional 
Facilities and Administrative (overhead) charges, such as budget officers, 
grant assistants, and building maintenance personnel, for administrative 
activities such as public relations, health or educational services unrelated 
to the research, and travel of investigators, other than the Fragile X 
Research Center Director, to scientific meetings.

o  Research Projects:  At least three independent research projects, each 
under a Research Project Leader, must be proposed.  Projects proposed for 
support in the Fragile X Research Center should provide evidence of 
integrated synergy reminiscent of that expected in more traditional program 
project (P01) grant mechanism applications. 

Funds requested for individual research projects to be supported by the Cores 
of the Fragile X Research Center should conform to PHS 398 R01 instructions 
and requirements (http://grants.nih.gov/grants/funding/phs398/phs398.html).  
For each research project, a budget for total costs of up to $250,000 per 
year may be requested.  However, for the purpose of this RFA, the budget 
should NOT be presented in modular grant format.   Support for the research 
projects proposed for the Fragile X Research Center may be requested for a 
period of up to five years.  However, funds for years beyond the duration of 
the applicant P30 MRDDRC will be contingent upon continued funding of the 
affiliated MRDDRC.

o  Research Project Leader:  The individual responsible for directing one or 
more of the Research Projects of the Fragile X Research Center.  The Research 
Project Leader may or may not be the Fragile X Research Center Director.

o  Support Core(s):  At least one separately budgeted component(s) that 
provide(s) support for the research programs must be proposed.  For the 
purposes of this RFA, use of core facilities located at other institutions is 
allowed and use of at least one Core at an existing, affiliated MRDDRC is 
required.  Applicants for the Fragile X Research Center must provide evidence 
of accomplishment and progress to date of the Core unit(s) in the existing 
MRDDRC, and anticipated accomplishments and progress that will be made by 
projects proposed for the Fragile X Research Center. 

Except for the Administrative Core, the Fragile X Research Center Cores may 
not duplicate the particular services of existing Cores of the affiliated 
MRDDRC.  Examples of Cores at existing MRDDRCs that investigators at the 
Fragile X Research Center might propose to access include, but are not 
limited to:  Genetics or Molecular Genetics Core, Behavioral Science Core, 
Information Technology Core, Design and Statistical Computing Core, Human 
Subjects Core, Data Management and Analysis Core, Participant Services Core, 
Quantitative and Observational Methodology Core, Genomics Core, Transgenic 
Mouse Core, Database and Biostatistics Core, and/or Longitudinal Studies and 
Statistical Modeling Core.  Applicants are encouraged to contact NICHD 
Program Staff prior to submission of the application to determine whether the 
Core services proposed for the Fragile X Research Center may represent 
duplication of Core services available at the proposed or affiliated MRDDRC.

For the purposes of this RFA, each Core must provide essential facilities and 
services to at least TWO component projects of the Fragile X Research Center 
at all times during the period of award.  This is an exception to the NICHD 
P30 Guidelines stating that each core should be utilized by three or more 
component projects.  If only one of the component projects requires proposed 
Core support, then the required expertise, technology, and/or infrastructure 
should be integrated into the relevant component project and the Core 
eliminated as a separate entity.

The application should provide:  (1) a plan for implementation of 
satisfactory quality-control systems for services and facilities for each new 
core proposed, (2) documentation of quality-control systems already in place 
for Cores being accessed at the MRRDRC, (3) evidence of cost-effectiveness 
through mechanisms such as fee-for-service, in-kind, or other means.  
Centralization should lower the costs that would be incurred if the 
individual research projects proposed had to provide the same facilities and 
services, and (4) evidence that the proposed cores will increase the quality 
and productivity of the research projects receiving core support.  

Budgets for Core units may include salaries for support core staff, supplies 
(including animals), scientific equipment, computer facilities and services, 
travel of technical and administrative staff for technical training that 
would enhance the quality of core unit operation or travel required to 
maintain the operation of the core unit, minor renovation of alteration of 
existing facilities, and consultation services.

o  Support Core Leader(s):  The individual responsible for directing a 
support Core facility. There may be one or more support Cores.  These Cores 
would provide services to achieve the research goals.  At least one of these 
individuals must be the Core Director of an existing and affiliated MRDDRC.

Annual Meetings

Due to the anticipated proprietary nature of the products under development, 
each Fragile X Research Center will act independently of the other.  The 
Fragile X Research Center Director should attend the annual meetings of the 
Directors of the MRDDRCs with NICHD staff.  Applications should include a 
request for funds to support attendance of the Fragile X Research Center 
Director at the annual meetings, as well as a statement of agreement to 
participate in these meetings.

PRE-APPLICATION WORKSHOP

An informational pre-application workshop addressing the scientific and 
administrative issues associated with this initiative will be held in April 
2002 in Bethesda, Maryland.  The purpose of the workshop is to (1) 
familiarize the potential applicant with established NIH guidelines and 
criteria for review, (2) discuss the areas of NICHD programmatic emphasis, 
and (3) facilitate the submission of a well-organized application.  Logistics 
information, including date, time and location, will be posted on the NICHD 
home page (http://www.nichd.nih.gov/RFA/HD-02-009/HD-02-009.htm) and may be 
obtained from program staff listed under INQUIRIES, below.

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 sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided indicating 
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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research, updated racial and ethnic categories in compliance with the new OMB 
standards, clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398, and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable, 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

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.

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.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances. Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at:  
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the names, addresses, telephone 
numbers, and institutions of the applicant, the Principal Investigator, i.e., 
the Director of the affiliated MRDDRC, and of the proposed Director of the 
Fragile X Research Center, the identities of other key personnel and 
participating institutions, and the number and title of this RFA.  Although 
the letter of intent is not required, is not binding, and does not enter into 
the review of a subsequent application, the information 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 by June 23, 
2002 at the address listed under INQUIRIES, below.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, E-mail:  GrantsInfo@nih.gov.

Application Instructions

Because the PHS 398 (rev. 5/2001) is designed primarily for the traditional 
R01 application, applicants will need to modify and expand several sections 
outlined in the PHS 398 instructions to provide the additional information 
required for a P30 Supplement application responsive to this RFA.  To ensure 
that the essential information is provided in a systematic fashion, all 
applications should be submitted in a format such as that outlined in 
Appendix I of the P30 guidelines.  Because the P30 supplement application 
requests funds for direct research support, each project must be presented in 
as much detail as if it were a request for an R01, within PHS 398 
page limitations.  
 
Applications submitted in response to this RFA should be prepared in 
accordance with the instructions presented in this RFA.  Information on the 
suggested format of applications may be found at 
http://www.nichd.nih.gov/funding/mechanism/p30_guide.cfm.

Submission Instructions

The RFA label available in the PHS 398 (rev. 5/01) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number HD-02-009.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note that 
this is in 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)

Applications delivered by individuals to the Center for Scientific Review 
will no longer be accepted.
	      
At the time of submission, two additional copies of the application and five 
sets of all appendices should be sent to:

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

Applications must be received by July 23, 2002.  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 CSR and for 
responsiveness to this RFA by NICHD 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 NICHD in accordance with the review criteria stated below.  
NO site visits will be made in the review of these applications, all 
information required for evaluation must be contained in the application.  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, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the National Advisory Child Health and Human 
Development Council.

Review Criteria

Peer review of the scientific and technical merit of these P30 supplement, 
Fragile X Research Center applications will focus on three areas:  (1) review 
of the individual component projects, 2) review of the individual cores, and 
(3) review of the program as an integrated effort and the overall merit of 
the program.   

The criteria listed in the NICHD P30 Guidelines, Appendix III, P30 Review 
Criteria, available at:  http://www.nichd.nih.gov/funding/mechanism/p30_guide.cfm, 
will be considered by reviewers in evaluating the proposed projects, cores, 
and the program as an integrated effort, as well as the overall merit of the 
program for all applications responding to this RFA.  With respect to these 
criteria and for the purposes of this RFA, "center" investigators and 
services refer to those individuals and services associated specifically with 
the proposed Fragile X Research Center, not necessarily with the MRDDRC P30 
Center as a whole. 

In addition, reviewers will evaluate:

o  institutional commitment at each site, when more than one institution is 
involved, 

o  the presence of administrative and organizational structure conductive to 
attaining the objectives of the "Center within a Center," the Fragile X 
Research Center,  

o  the leadership ability and scientific stature of both the Principal 
Investigator, who is the Director of the MRDDRC, and the Co-Investigator, who 
is the proposed Director of the Fragile X Research Center, their abilities to 
meet their respective program"s demands of time and effort, and their ability 
to promote the mission of both the Fragile X Research Center and the 
affiliated MRDDRC.  

Schedule

Letter of Intent Receipt Date:    June 23, 2002
Application Receipt Date:         July 23, 2002
Peer Review Date:                 October/November 2002
Council Review:                   January 2003
Earliest Anticipated Start Date:  April 2003
            
AWARD CRITERIA

Criteria that will be used to make award decisions include scientific and 
technical merit as determined by peer review, programmatic priorities and 
relevance, program balance, and the availability of funds.  

INQUIRIES

Potential applicants are strongly encouraged to contact program staff early 
in application development with any questions regarding the responsiveness of 
their proposal to the goals of this RFA.  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:

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) 496-1383
FAX:  (301) 496-3791
E-mail:  mo96o@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Mary E. Daley
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) 496-1305
FAX:  (301) 402-0915
E-mail:  md74u@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.865.  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 inter-governmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service strongly encourages all grant 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 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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