Release Date:  January 12, 1999

PA NUMBER:  PAS-99-037


National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke


The Mental Retardation and Developmental Disabilities (MRDD) Branch, Center for
Research for Mothers and Children (CRMC), of the National Institute of Child
Health and Human Development (NICHD) and the Division of Fundamental Neuroscience
and Developmental Disorders (DFNDD) of the National Institute of Neurological
Disorders and Stroke (NINDS) invite research grant applications that address the
genetics, pathophysiological mechanisms, and the development of biomarkers for
Rett Syndrome.  Areas of interest include developmental neurobiology,
pathophysiology, genetics, epidemiology, structure-function correlations, and
clinical studies that have a direct link to Rett Syndrome.  Specific funds will
be set aside to support investigator-initiated applications responsive to this
grant solicitation.


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 Program Announcement (PA), Rett
Syndrome:  Genetics, Pathophysiology, and Biomarkers, is related to the priority
area chronic disabling conditions.  Potential applicants may obtain a copy of
"Healthy People 2000" at


Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State or local governments, and eligible agencies of the
Federal government.  Foreign institutions and organizations may use the R01 or
R21 mechanisms, but are excluded from applying for the R03 mechanism. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.


This PA will use the NIH Research Project Grant (R01), Small Grant (R03), and
Exploratory/Developmental Grant (R21) mechanisms.  All applications will be
reviewed according to the customary NIH peer-review procedures.  Responsibility
for the planning, direction, and execution of the proposed project will be solely
that of the applicant.  The total project period for R01 applications submitted
in response to this PA may not exceed five years; for R03s, the total project
period may not exceed two years nor a maximum of $50,000/year direct costs; for
R21s the total project period may not exceed three years nor a maximum of
$100,000/year direct costs.  Relevant applications and renewals are welcome
throughout the three-year duration of this PA.  


During the course of this program announcement, NICHD and NINDS will contribute
up to a total of $1.5 million in total (direct plus facilities and
administrative) costs (NICHD:  $750,000 and NINDS:  $750,000) to support research
grants responsive to this PA.  The number of awards to be made depends on the
overall scientific merit of the applications and the availability of funds
throughout the duration of this solicitation.


The MRDD Branch of NICHD supports research that relates to the biological,
behavioral and social processes that contribute to, or influence the development
of, mental retardation and developmental disabilities.  Prevention of mental
retardation and developmental disabilities and amelioration of the clinical
manifestations of those afflicted constitute areas of special emphasis within the
MRDD Branch.

The DFNDD of NINDS supports fundamental and clinical research in developmental
neurobiology to promote the understanding of the processes of normal and abnormal
brain development and to bring about the capabilities of effective, rational
treatments, interventions, and prevention of neurodevelopmental disorders.

Research on more general aspects of  autism spectrum disorders is supported by
several institutes at NIH:  National Institute of Child Health and Human
Development (NICHD),  National Institute of Mental Health (NIMH), National
Institute of Neurological Disorders and Stroke (NINDS), and National Institute
on Deafness and Other Communication Disorders (NIDCD).  For further information
on support of autism research, as well as specific institute contacts, see
Announcement PA-98-108, "Research on Autism and Autism Spectrum Disorders."

Rett Syndrome is a severely disabling neurodevelopmental disorder that affects
1 in 10-15,000 females. Despite intense research efforts, little progress has
been made in understanding the cause of this disorder and in developing
approaches for treatment.  Currently, there are no genetic or biochemical markers
for Rett Syndrome; it is diagnosed solely on the basis of clinical criteria. 
Rett Syndrome has defied traditional genetic and neuropathological approaches
that have provided insights into other neurological disorders. Although the vast
majority of cases appear to be sporadic, current data suggest a genetic basis,
possibly associated with the X chromosome.  Subtle structural and neurochemical
abnormalities have been described in Rett brains, but they have not been put
together into a specific pathophysiological or neurodevelopmental mechanism. 
Understanding the etiology of Rett Syndrome is necessary for developing
therapeutic strategies, as well as for providing a clear diagnosis.  It is also
possible that Rett Syndrome may represent a novel paradigm for neurogenetic
diseases, abnormalities in neurodevelopmental processes, and postnatal brain

This PA focuses on neurobiological studies relevant to understanding the genetic
and pathophysiological basis of Rett Syndrome and for developing reliable
biological markers.  Applications submitted in response to this PA may address
one or more of the following topics in the context of Rett Syndrome: 

o  Epidemiological studies to characterize the environmental and/or genetic basis
of Rett Syndrome, including studies of the rare familial cases or contrasting
familial and sporadic cases;

o  Neurodevelopmental and longitudinal studies to characterize the
neuropathological progression and inherent variability in this disorder in order
to develop specific hypotheses about the initial (primary) abnormality;

o  Studies of other neurological conditions and clinical abnormalities that co-
occur in the families of individuals with Rett Syndrome, which may have some
common biological or environmental basis;

o  Histological, neurochemical, brain-imaging, and structure-functional studies
to define the molecular, cellular, and/or biochemical basis of this disorder;

o  Studies of tissues, cells, and DNA isolated from affected individuals, in
order to develop specific hypotheses about the basic abnormalities involved in
Rett Syndrome;

o  Studies on genetic mechanisms, candidate genes, and chromosomal regions that
have been implicated in Rett Syndrome; this may include relevant studies of X-
inactivation, imprinting, positional effects, and gender-specific aspects of gene

o  Studies on potential gender-specific mechanisms (e.g., genetic, hormonal,
neurodevelopmental) that may explain the apparent occurrence of Rett Syndrome
solely in females;

o  Studies to define specific biological markers that would be useful for the
diagnosis, screening, and/or treatment of Rett Syndrome;

o  Hypothesis-based therapeutic strategies for managing the devastating
symptomatology of Rett Syndrome;

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


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

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been 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 are available on the web at the following URL


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

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

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


Applications are to be submitted on the grant application form PHS 398 (rev.
4/98).  Additional instructions for R03 and R21 applications are described below. 
Applications will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research; from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda MD 20892-7910, telephone 301/710-0267, Email:;
and from the following website:

Applicants planning to submit grant applications requesting $500,000 or more in
direct costs for any year, regardless of whether it is a new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
these types, are advised that they must contact NICHD or NINDS program staff
before submitting the application, i.e., as plans for the study are being
developed.  Furthermore, the applicant must obtain agreement from the NICHD or
NINDS staff that the Institute will accept the application for consideration for
award.  Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute (NICHD or NINDS) who agreed to accept
assignment of the application.

This policy requires applicants to obtain agreement for acceptance of any such
application as well as any subsequent revisions or  amendments.  Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at:

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.  Under this
mechanism, applicants may request up to two years of support and up to a maximum
of $50,000 direct costs per year.  R03 grants are non-renewable, and may not be
used to supplement an ongoing project.  R03 applicants must follow the
application guidelines for the NICHD Small Grants Program (NIH Guide, Vol. 25,
No. 3, February 9, 1996, PA-96-025).  Line two of the face page should reference
"PA-96-025, NICHD Small Grants Program" in addition to the Rett Syndrome PA.  A
Just-in-Time application format is required.  Detailed Budget and
Other Support sections are not to be submitted with the initial application.  The
research plan is limited to ten pages, and no appendix material may be submitted.

The Exploratory/Developmental (R21) research mechanism should be used for support
of creative, novel, and/or high risk/high payoff approaches that could produce
innovative advances in this field.  This includes feasibility studies, protocol
planning, and the incorporation of new disciplines and technologies.  Applicants
may request up to three years of support and up to a maximum of $100,000 direct
costs per year.  R21 grants are non-renewable, and may not be used to supplement
an ongoing project.  The following guidelines must be followed for R21
applications.  Line two of the face page should reference "NINDS R21 Mechanism"
in addition to the Rett Syndrome PA.  Under Description, the applicant must
identify the specific research concept or methodology to be developed and/or
explored, as well as its innovation, and the expected impact on Rett research. 
The Research Plan, Items a-d, may not exceed 15 pages including tables and
figures. However, the 15-page limitation does not include Items e-i (Human
Subjects, Vertebrate Animals, Literature Cited, Consortia,
Consultant/Collaborators).  Color illustrations or color photographs may be
included as an appendix, but only if black-and-white copies of these figures
appear in the body of the application; no other appendix material is permitted. 
Applications exceeding the page limitation or NIH requirements for type size and
margins (refer to PHS 398 instructions) will be returned to the applicant without
consideration. Preliminary data are not required, but when available should be
included.  The Research Plan must be soundly developed in the context of the
current knowledge/research base of Rett Syndrome, with well-defined and clear
objectives.  The Approach should utilize appropriate concepts and current
methodology. Applicants should elaborate on innovative aspects of the proposed
research, novel collaborations, and special attributes of the resources and
environment.  In addition, applicants must identify how the exploratory studies
could result in new insights or capabilities for research into Rett Syndrome and
more general aspects of neurodevelopmental disorders.

The title and number of this program announcement 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 or computer-generated original of the application, 
including the Checklist, and five signed photocopies in one package to:

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

This PA covers applications received from February 1, 1999 through March 1, 2002.
Applications received after this date will still be reviewed but may not receive
special consideration with set aside funds.  The Center for Scientific Review
(CSR) will not accept any application in response to this PA 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 an application already reviewed, but such
applications must include an introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by CSR and for
responsiveness by NICHD and NINDS staff.  Incomplete applications will be
returned to the applicant without further consideration.  All complete
applications will be assigned on the basis of established NIH referral
guidelines.  Applications will be evaluated for scientific and technical merit
in the appropriate study sections in accordance with the standard NIH peer review
procedures.  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, generally the top half of applications
under review, will be discussed, assigned a priority score, and receive a second
level review by the appropriate national advisory council.  The anticipated date
of the award is September 1999.

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 important work that by its nature is 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

(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 will also 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 will also 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.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.


In addition to the scientific and technical merit of the applications, the
following factors will be considered in making awards:

o  quality of the proposed project as determined by peer review
o  availability of funds
o  program priority


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

Direct inquiries regarding programmatic and scientific issues to:

Ralph M. Nitkin, Ph.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B-09
Bethesda, MD  20892
Telephone:  (301) 496-1385
FAX:  (301) 496-3791 

Giovanna M. Spinella, M.D.
Division of Fundamental Neuroscience and Developmental Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 8C10
Bethesda, MD  20892
Telephone:  (301) 496-5821
FAX:  (301) 402-0887

Direct inquiries regarding fiscal matters to:

Edgar D. Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A-17
Bethesda, MD  20892
Telephone:  (301) 435-6999
FAX:  (301) 402-0915

Karen D. Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue,Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219


This program is described in the Catalog of Federal Domestic Assistance No.
93.865 Research for Mothers and Children.  Awards are made under the authority
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.

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 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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