Full Text AR-93-004

MYCOPLASMA AND OTHER INFECTIOUS AGENTS AS A CAUSE FOR RHEUMATIC
DISEASES

NIH GUIDE, Volume 22, Number 1, January 8, 1993

RFA:  AR-93-004

P.T. 34

Keywords: 
  Rheumatic Diseases 
  Fungal Diseases+ 
  Infectious Diseases/Agents 
  Autoimmunity 
  0715126 


National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  March 5, 1993
Application Receipt Date:  April 8, 1993

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAID) and the National Institute of Allergy and Infectious
Diseases (NIAID) invite applications for research aimed at studying
the possible causal relationship between mycoplasma and other
infections and the chronic systemic rheumatic diseases.  The goal of
the Request for Applications (RFA) is to investigate whether any of
the chronic inflammatory rheumatic diseases might be caused by
infection, and if so, which infection and by what mechanisms.

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,
Mycoplasma and Other Infectious Agents as a Cause for 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.
Minority individuals and women are encouraged to submit applications
as Principal Investigators.  Foreign institutions are not eligible
for First Independent Research Support and Transition (FIRST) (R29)
awards.

MECHANISM OF SUPPORT

The mechanism of support for this RFA will be the National Institutes
of Health (NIH) research project grant (R01) and the FIRST (R29)
award.  Responsibility for the planning, direction, and execution of
the proposed research will be solely that of the applicant.  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 vary also.
In addition to the requirements stated in this RFA, awards will be
administered under PHS grants policy as stated in the Public Health
Service Grants Policy Statement, DHHS Publication No. (OASH)
90-50-000, revised October 1, 1991.  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.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
within the application.

FUNDS AVAILABLE

Up to $925,000 for the first-year and additional approved expenses
for up to five years has been committed to fund applications
submitted in response to this RFA.  The NIAMS and the NIAID plan to
make approximately three to four and one to two awards, respectively,
in FY 1993, contingent upon receipt of highly meritorious
applications.  Funding beyond the first and subsequent years of the
grant will be contingent upon satisfactory progress during the
preceding years and the availability of funds.

RESEARCH OBJECTIVES

The chronic systemic rheumatic illnesses constitute an important
burden for the United States.  They disproportionately affect women
and minority populations.  These illnesses include rheumatoid
arthritis, which is estimated to affect up to two percent of all
Americans, systemic lupus erythematosus, juvenile arthritis, and
ankylosing spondylitis and Reiter's syndrome.  These illnesses share
characteristic immunologic abnormalities; pathologically they
demonstrate sterile inflammation, i.e., inflammation in which no
infectious agent has been consistently identified.  Nonetheless,
based on both anatomic pathology and on clinical characteristics,
suspicion remains that infectious agents including mycoplasma may
play an important role in the development of these illnesses.

In the recent past, several systemic rheumatic diseases have been
demonstrated to be associated with infection, though the precise
relationship between infection and the rheumatic illness is not yet
known.  The associations include that of hepatitis B infection with
systemic necrotizing vasculitis (polyarteritis nodosa), hepatitis C
infection with IgG-IgM cryoglobulinemia, and the documentation that
an epidemic form of arthritis, primarily in children, is caused by
infection with a previously unidentified spirochete Borrelia
burgdorferi.  Such findings have given impetus to the concept that
infection can, in fact, trigger rheumatic illness.  Mycoplasma has on
occasion been suspected to be a trigger, but this hypothesis remains
controversial. Autoantibodies frequently found in patients with
rheumatic illness parallel antibodies that occur in a variety of
infectious illnesses.  The identification of potential microbial
triggering agents for the reactive arthritis and for the
spondyloarthropathies and a demonstration of the potential molecular
relationships between the HLA B27 histocompatibility antigen and
certain enteric pathogens gives further support to the hypothesis
that infection triggers rheumatic diseases.

The identification of pathogenic organisms, or description of the
relationship between acute or persistent infections and chronic
rheumatic illness, will lead to dramatic changes in current concepts
of therapy and may lead as well to effective preventive measures.
This RFA, therefore, seeks research projects that will advance
knowledge in this field.

Appropriate research areas may include, but are not limited to:

o  Identification of the role of and mechanisms used by pathogenic
organisms such as mycoplasma in the induction and maintenance of
self-reactivity and immune dysregulation in rheumatic diseases.

o  Studies on the effects of infection on self antigen processing and
presentation, inflammatory cytokine and antibody production, and
function of regulatory cells in human and experimental systems of
rheumatic diseases, with emphasis on the mechanisms and molecular
events mediating those effects.

o  Analysis of the relative contribution of the organism life cycle,
products, components and the elicited host responses to the induction
and maintenance of self-reactivity, immune dysregulation and tissue
damage in rheumatic diseases.

o  Studies on the mechanisms involved in changes in the local
environment induced by the pathogenic organisms and their products
that lead to immune self-reactivity and tissue injury.

o  Development of new animal models of human chronic rheumatic
diseases to establish the role of infectious agents in the etiology
and pathogenesis of disease and to serve as models for therapeutic
intervention.

o  Studies of the molecular basis for observed associations of HLA
haplotypes and infection in rheumatic diseases and design of
molecular approaches to manipulate this interaction to affect disease
outcome.

o  Pilot studies of new forms of prevention and treatment of
rheumatic diseases using anti-microbial agents to demonstrate
feasibility for possible multicenter clinical trials.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in SectionS 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups must
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' population, including
minorities.

If the required information is not contained within the application,
the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 5, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

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

The letter of intent is to be sent to:

Dr. Tommy Broadwater
Chief, Review Branch, Extramural Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 404
Bethesda, MD  20892
Telephone:  (301) 496-0754

APPLICATION PROCEDURE

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Inquiries, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD
20892, telephone 301/496-7441.

The RFA label available in the application kit must be affixed to the
bottom of the face page.  Failure to use the 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 check the YES box.

The completed and signed, typewritten original application and three
signed, exact, clear, single-sided photocopies must be sent or
delivered in one package to:

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

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

Dr. Tommy Broadwater
Chief, Review Branch, Extramural Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 404
Bethesda, MD  20892

Applications must be received by April 8, 1993.  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.  However, it is
allowable to submit the same project as both an R01 and as a
component project of a program project (P01).  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 previously reviewed.  Such applications
must not only include an introduction addressing the previous
critique but also be responsive to this RFA.

REVIEW PROCEDURES

Upon receipt, applications will be reviewed by the DRG for
completeness. Incomplete applications will be returned to the
applicants without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIAMS staff function.  If the application is not responsive
to the RFA, NIAMS staff will contact the applicant to determine
whether it should be returned to the applicant or held until the next
regular receipt date and reviewed in competition with all other
unsolicited applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific and
technical merit by an appropriate peer review group convened by the
NIAMS.  Applications may be subject to triage by an NIAMS peer review
group to determine scientific merit relative to other applications
received in response to this RFA.  If the number of applications
submitted is large compared to the number of awards to be made, a
preliminary scientific peer review may be conducted and applications
withdrawn from further competition if not competitive for the award.
The NIAMS will notify the applicant and institutional official of
this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA.  Following initial review, applications will receive a
second level review by the National Arthritis and Musculoskeletal and
Skin Diseases Advisory Council or the National Allergy and Infectious
Diseases Advisory Council unless not recommended for further
consideration by the initial review group.

Review criteria for RFAs are generally similar as those for
unsolicited investigator-initiated research grant applications and
include:

o  Scientific and technical merit criteria specific to the objectives
of the RFA;

o  Scientific, technical, or medical significance and originality of
the proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to conduct the research;

o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  Availability of resources necessary to perform the proposed
research;

o  Appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

In addition, for foreign applications, the following criterion
applies:

o  Uniqueness of research such that it can only be performed outside
of the United States.

Schedule

Letter of Intent Receipt Date:  March 5, 1993
Application Receipt Date:       April 8, 1993
Initial Review:                 June 1993
Second Level Review:            September 9, 1993
Anticipated Date of Award:      September 30, 1993

AWARD CRITERIA

Applications will compete for available funds with all other
applications responsive to this RFA.  The following items will be
considered in making funding decisions:

o  Quality of the proposed project as determined by peer review;
o  Availability of funds; and
o  Program balance among research areas represented in this RFA.

The anticipated date of award is September 30, 1993.

INQUIRIES

Written and telephone inquiries regarding this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Susana A. Serrate-Sztein
Director, Arthritis Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 405
Bethesda, MD  20892
Telephone:  (301) 402-3340

Dr. Howard Dickler
Chief, Clinical Immunology Branch
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A10
Bethesda, MD  20892
Telephone:  (301) 496-7104
FAX:  (301) 402-2571

Direct inquiries regarding fiscal matters to:

Diane M. Watson
Chief, Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 732A
Bethesda, MD  20892
Telephone:  (301) 402-3352

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.846, Arthritis, Musculoskeletal and Skin Diseases
Research and No. 93.855, Allergy, Immunology and Transplantation
Diseases Research.  Awards will be made under the authority of the
Public Health Service Act, Title III, Section 301 (Public Law 410,
78th Congress, as amended, 42 USC 241) 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.

.

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