Full Text AR-93-005

RESEARCH ON CAUSAL MECHANISMS IN SYSTEMIC LUPUS ERYTHEMATOSUS

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

RFA:  AR-93-005

P.T. 34

Keywords: 
  Autoimmunity 
  Etiology 
  Biology, Molecular 
  Genetics 
  Immunology 


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 (NIAMS) and the National Institute of Allergy and Infectious
Diseases (NIAID) invite applications focused on the mechanisms and
causes of tissue injury in systemic lupus erythematosus (SLE).  The
goals of the research are to identify and analyze the factors and
mechanisms of tissue injury not only in the kidneys but in the brain
and other organs, using advanced molecular, genetic, and
immunological approaches; to develop new experimental systems to
study and test the pathogenicity of human autoantibodies and
autoreactive cells related to lupus; to elucidate the genetic factors
important in the development of the illness; and to characterize the
mechanisms involved in induction or exacerbation of disease by
environmental factors.

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 Request
for Applications (RFA), Research on Causal Mechanisms in Systemic
Lupus Erythematosus, 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 mechanisms 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.  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, 1993.  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 $1,925,000 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 seven to ten 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

Systemic lupus erythematosus (SLE) is an acute and chronic illness
predominantly affecting young women, and affecting Afro-Americans
disproportionately to Americans of European descent.  This illness is
characterized by a wide array of humoral and cellular immunological
abnormalities involving both up-regulation and down-regulation of
critical elements of the immune system.  The order in which
components of immunological dysregulation occur, i.e., which is a
primary and which is secondary event, is not well understood.  In
some cases, the defective immune responses may be genetically
determined.  The occurrence of SLE is clearly related to the
inheritance of a specific HLA types and C4 complement types, but not
all persons with the characteristic genetic background are affected.
To the contrary, identical twins discordant for disease are regularly
seen, suggesting that environmental factors contribute to the
disease.  Whether these external factors induce the initial
occurrence of the disease or are responsible for subsequent flares of
the illness is unknown.

An immunological model of the illness has dominated thinking for the
past several decades.  This model invokes the occurrence of
autoantibodies (primarily to double-stranded DNA), the formation of
immune complexes consisting of these antibodies and their antigens,
the deposition of these complexes in vulnerable areas, such as the
glomerular basement membrane, inducing complement-dependent tissue
injury.  This model has not satisfactorily explained many forms of
injury seen in patients with lupus, including neurological and
cardiac pathology and coagulation abnormalities.  Other forms of
tissue injury have occasionally been identified.  These latter forms
include the activities of cytotoxic antibodies, pathological
regulation of a variety of cytokines, coagulation abnormalities
leading to non-inflammatory vascular occlusion, and other phenomena.
It is the purpose of this RFA to explore these additional causes.

The RFA requests individual research projects (R01 and R29) that
focus on questions relevant to defining the causes of the disease and
mechanisms of tissue injury in SLE.  Appropriate research areas
include, but are not limited to:

o  Design and use of new experimental systems to dissect the events
leading to immune dysregulation in human lupus and analysis of their
relative contribution to predisposition, onset and severity of
disease.

o  Development of new experimental systems of human lupus to study
pathogenicity of autoantibodies, autoreactive, accessory and
regulatory cells and factors.

o  Analysis of the fine molecular characteristics and mechanisms
involved in tissue damage by immune complexes, including new systems
to test for pathogenicity of human autoantibodies and immune
complexes.

o  Studies of immune and non-immune mechanisms involved in cardiac
and neurological pathology including development and use of new
experimental models of these manifestations in human lupus.

o  Studies of the molecular basis for specificity and pathogenicity
of cytotoxic antibodies with emphasis on the identification of
critical sites and/or activities involved in tissue injury.

o  Characterization of the genetic and molecular mechanisms involved
in cytokine dysregulation in lupus and elucidation of the mechanisms
by which cytokine dysregulation leads to tissue injury and clinical
disease.

o  Identification and characterization of the molecular components
and mechanisms that initiate vascular injury in lupus.

o  New approaches to study coagulation abnormalities including
antiphospholipid antibody and the mechanisms leading to
noninflammatory vascular occlusion and other phenomena of the
antiphospholipid antibody syndrome.

o  Studies on the molecular mechanisms involved in induction and
exacerbation of disease caused by environmental factors.

o  Studies on the environmental factors that may induce the illness
or its exacerbation.

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 must 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 asses s 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 should
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' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

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 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 statement, "submitted in response to AR-93-005,
RESEARCH ON CAUSAL MECHANISMS IN SYSTEMIC LUPUS ERYTHEMATOSUS".

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 and NIAID 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, RESEARCH ON CAUSAL
MECHANISMS IN SYSTEMIC LUPUS ERYTHEMATOSUS AR-93-005, must be typed
on line 2a of the face page of the application form and the YES box
should be checked.

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.  The National Institute of Environmental
Health Sciences has primary interest in toxicological influences of
the immune system. Applications of this description may be referred
to that Institute.

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 Branch
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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