Full Text AR-95-001

PATHOGENESIS OF PEDIATRIC RHEUMATIC DISEASES

NIH GUIDE, Volume 23, Number 41, November 25, 1994

RFA:  AR-95-001

P.T.


Keywords: 


National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  February 6, 1995
Application Receipt Date:  April 21, 1995

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) invites applications for basic research on the
pathogenesis of pediatric rheumatic diseases.  The goal of this
Request for Applications (RFA) is to promote research on the genetics
basis for disease predisposition and on the immunologic and
biochemical mechanisms leading to pediatric rheumatic diseases and
their clinical manifestations.  The research will improve knowledge
of the diseases and will identify critical processes and mediators
that could be used to establish a rational basis for new and
effective treatments.  Multidisciplinary approaches that apply
current basic science approaches to the study of rheumatic diseases
of childhood through formal collaborations are strongly encouraged.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Pathogenesis of Pediatric Rheumatic Diseases, is related to the
priority area of chronic disabling conditions.  Potential applicants
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

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 are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women and persons with disabilities are encouraged to
apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) awards and the
interactive research project grant (IRPG) mechanisms.  Responsibility
for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  The total project period for
applications submitted in response to the present RFA may not exceed
five years.  The anticipated award date is September 30, 1995.
Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
also vary.  This RFA is a one-time solicitation.  Future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is $1.5 million.  Funding is
contingent upon receipt of scientifically meritorious applications.
The NIAMS expects to fund five to eight new awards.

The National Institute of Allergy and Infectious Diseases (NIAID) is
interested in basic research on rheumatic diseases of children,
including the interaction between the endocrine and the immune
systems.  Applications that are of mutual interest are likely to be
given secondary assignment to the NIAID in accordance with Division
of Research Grants (DRG) referral guidelines.

RESEARCH OBJECTIVES

Background

The rheumatic diseases of childhood, including juvenile rheumatoid
arthritis (JRA), rheumatic fever, systemic lupus erythematosus,
juvenile dermatomyositis, scleroderma, and vasculitis, present unique
clinical and research challenges.  Combined, the rheumatic diseases
are the most common form of chronic diseases of childhood, and they
are major causes of disability.  The pediatric forms of rheumatic
disease differ clinically from their counterparts in adults and
current evidence suggests that the underlying mechanisms leading to
disease may be different as well.  For example, pauciarticular
juvenile rheumatoid arthritis has complex associations with genes
encoding components of the major histocompatibility complex that do
not correspond to the associations found in the adult forms.  Other
mechanisms that appear to play a role in adult rheumatoid arthritis,
such as restrictions in the use of certain V beta gene families for
the T cell receptors, have not been proven in JRA.  Other disease
manifestations possibly related to the onset of diseases before
completion of skeletal development, such as decreased bone mass and
delayed growth, also point to different pathogenic mechanisms.

The current status and future directions of pediatric rheumatology
were the subject of a workshop sponsored by the NIAMS held in
September 1994.  The workshop brought together a group of clinicians
and scientists working in the field of pediatric rheumatic diseases
to review the biomedical problems facing the pediatric rheumatology
community and to identify the areas that can be addressed with
current methodologies.  In addition to recommending the creation of
disease registries, the group emphasized the need for the development
of a basic research base as a fundamental step to advance
understanding of the diseases.  The experts identified the research
areas that offered the most promising opportunities for research.
Those critical areas are the focus of this solicitation.

The areas of research interest include:

o  Studies on the genetic factors influencing predisposition, onset,
and disease severity, including studies on the localization of genes
and characterization of the biological activity of gene products in
the pathogenesis of the disease;

o  Analysis of immunopathogenic mechanisms, including the biochemical
and biological characterization of self-antigens, the mechanisms of
self-antigen presentation, and the role of antigen-presenting cells
in the initiation and perpetuation of disease;

o  The development of technologies to explore the pathogenicity of
cells that react with antigens that directly or by cross reactivity
may induce autoimmune responses;

o  The role of hormones and neuroendocrine factors in the loss of
self-tolerance and in the evolution of disease as identified by in
vitro tests of disease activity, such as cell-mediated responses or
antibody production;

o  The mechanisms involved in progression and remission of disease,
with emphasis on the identification of molecular mediators that may
enhance responses leading to remission;

o  Studies of bone metabolism, bone mass, and growth in the context
of juvenile rheumatic arthritis or in patients with other rheumatic
diseases in which there is delayed growth because of the disease or a
complication/adverse effect of treatment.

This list is illustrative and not exclusive or restrictive.
Applications combining multidisciplinary approaches  focused on
research hypotheses derived from previous research on pediatric
diseases or in diseases of the adult that may be extended to the
pediatric forms are encouraged.  Collaborations between basic
research teams investigating aspects of pathogenesis that may not
have been previously applied but that may be relevant to pediatric
rheumatic diseases are also encouraged.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which were published in the Federal
Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the
NIH Guide for Grants and Contracts of March 18, 1994, Volume 23,
Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRES.  Program staff
may also provide additional relevant information concerning the
policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 6, 1995, a
letter of intent that includes a title of the proposed research, the
name, address, and telephone number of the Principal Investigator,
the identities of other key personnel and participating institutions,
and the number and title of the RFA in response to which the
application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows NIAMS staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

Susana A. S. Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-37G
45 Center Drive MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 480-4543

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714 and from the program administrator listed
under INQUIRES.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
line 2a of the face page of the application form and the YES box must
be marked.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

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

Tommy L. Broadwater, Ph.D.
Grants Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-25E
45 Center Drive MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4952
FAX:  (301) 480-4543

Applications must be received by April 21, 1995.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by NIAMS staff.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, DRG staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.  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
NIAMS in accordance to the review criteria listed below.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined non-competitive
will be withdrawn from further consideration and the Principal
Investigator and the official signing for the applicant organization
will be notified.

The second level of review will be provided by the National Advisory
ICD Council/Board.

Review criteria for this RFA are generally the same as those for
unsolicited research grant applications:

o  scientific, technical, or clinical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff and collaborations;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research.

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.  The initial review group will also examine the provisions
for the protection of human and animal subjects, the safety of the
research environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.

AWARD CRITERIA

The anticipated date of award is September 30, 1995.  Awards will be
based upon the following criteria:

o  scientific merit
o  availability of  funds
o  programmatic priorities of NIAMS

INQUIRIES

Written and telephone 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:

Susana A. S. Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-37G
45 Center Drive MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (310) 480-4543
Email:  arthrit@ep.niams.nih.gov

Direct inquiries regarding fiscal matters to:

Diane Watson
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-53
45 Center Drive MSC 6500
Bethesda, MD  20892-6500
Telephone:  (310) 594-3505
FAX:  (310) 480-5450
Email:  watsond.ep.niams.nih.gov

Schedule

Letter of Intent Receipt Date:  February 6, 1995
Application Receipt Date:       April 21, 1995
Initial Review:                 June 1995
Second Level Review:            September 1995
Anticipated Award Date:         September 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.361.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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