SPONDYLOARTHROPATHIES: NEW APPROACHES TO PATHOGENESIS

Release Date:  December 12, 2000

RFA:  AR-00-008

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Eye Institute

Letter of Intent Receipt Date:  January 2, 2001
Application Receipt Date:       March 13, 2001

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) and the National Eye Institute (NEI) invite applications for research
on the pathogenesis of ankylosing spondylitis (AS) and related diseases and on
the development of innovative therapeutic approaches.  The applications may be
for individual research projects (R01) or for exploratory/developmental grants
(R21).  The objective of the exploratory/developmental mechanism (R21) is to
encourage applications from individuals who are interested in testing
innovative or conceptually creative ideas that are scientifically sound and
may advance our understanding of these diseases.  AS is a rheumatic disease
characterized by inflammation of the tendons and ligaments around the bones
and joints in the spine producing pain, deformity, and disability, and this
condition can also affect other articular and non-articular sites.  Studies on
pathogenesis of psoriatic arthiritis, inflammatory bowel disease, and reactive
arthritis (Reiter's syndrome) including ocular involvement like uveitis,
iritis, and conjunctivitis are included in this RFA.  This RFA is based in
part on the scientific opportunities identified in the conference "Ankylosing
Spondylitis Research: HLA-B27 and Beyond."  A summary of the conference and
research questions raised can be found at:
(http://www.nih.gov/niams/reports/b27summ.htm)

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 several
objectives, particularly those listed in the chapter "Arthritis, Osteoporosis,
and Chronic Back Conditions."  Potential applicants may obtain "Healthy People
2010" at http://www.health.gov/healthypeople.   The two overarching goals of
Healthy People  2010 are to:  1) increase quality and years of healthy life,
and 2) eliminate health disparities.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public or 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 to apply for
these grants; however, applicants may collaborate, through consultation or
contractual agreements, with investigators at foreign institutions. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanisms of support will include the investigator-initiated research
project grant (R01) and the exploratory/developmental research grant (R21).

R21 Applications.  Use of this mechanism is recommended by investigators
experienced in spondylitis research who wish to adapt new methodologies to
develop scientific approaches and models to study the pathogenesis, and to
gather pre-clinical data of new therapies or to gather preliminary data on
toxicity and potential efficacy in a limited number of patients.  Also
encouraged to apply are investigators with expertise in fields other than
spondylitis who wish to establish new research programs on the disease.

Exploratory/developmental studies are not intended for large scale
undertakings nor to support or supplement ongoing research.  Instead,
investigators are encouraged to explore the feasibility of an innovative
research question or approach which may not be justifiable through existing
research to compete as a standard research project grant (e.g., R01), and to
develop a research basis for a subsequent application through other
mechanisms, i.e., R01, P01.

Exploratory/developmental (R21) grants, may not exceed $75,000 per year in
direct costs.  The total project period for an R21 application submitted in
response to this RFA may not exceed three years.  These grants are
non-renewable and continuation of projects developed under the R21 program
will be through the traditional unsolicited (R01 or P01) grant programs.

Investigators proposing to conduct small, pilot/toxicity clinical trials are
advised to review the NIAMS guidelines for preparation of clinical trial
applications and the NIAMS guidelines for Data and Safety Monitoring Boards
(http://www.nih.gov/niams/grants/datasafe.htm.)

R01 Applications.  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.   Modular budgeting procedures apply for grants up to
$250,000.  Specific R01 application instructions have been modified to reflect
"Modular grant" and "Just-in-time" streamlining efforts.  Complete
instructions and information on Modular Grants can be found at
(http://grants.nih.gov/grants/funding/modular/modular.htm).

Investigators who wish to establish new collaborative research programs with
laboratories at the NIAMS, and apply for funding under this RFA, are
encouraged to contact Dr. Barbara Mittleman, Director, Office of Scientific
Interchange, NIAMS (mittlemb@mail.nih.gov)

FUNDS AVAILABLE

It is anticipated that for FY 2001, approximately $1.5 million total costs
will be available for the first year of support for this initiative.  The
specific number to be funded will depend on the merit and scope of the
applications received and on the availability of funds.  Applicants may
request up to five years of support for the R01.  Direct costs will be awarded
in modules of $25,000, less any overlap or other necessary administrative
adjustments.  Facilities and Administrative costs will be awarded based on the
negotiated rates.

Exploratory/developmental (R21) grants, may not exceed $75,000 per year in
direct costs, including indirect costs for collaborating institutions, if any. 
The total project period for an R21 application submitted in response to this
RFA may not exceed three years.  These grants are non-renewable and
continuation of projects developed under the R21 program will be through the
traditional unsolicited (R01 or P01) grant programs.

RESEARCH OBJECTIVES

Ankylosing Spondylitis is a painful, deforming, inflammatory disease that
leads to spontaneous fusion of the vertebra. It often manifests itself as low
back pain or sacroiliac joint arthritis and affects, to a variable extent,
other joints and soft tissues.  Its pathogenesis is poorly understood, and
current therapy inadequately prevents deformity and disability.  As is
strongly associated with HLA-B27; however, the presence of this class I major
histocompatibility (MHC) marker does not uniformly result in disease. 
Currently, much effort is being expended to understand the immune inflammatory
component and the relationship to HLA-B27 and other MHC genes in AS and
related diseases.  Some investigations suggest that interactions between B27
and bacterial products are involved in the pathogenesis of disease.  While
these studies strengthen the association of MHC loci and the development of
AS, there are relatively few studies on the cellular and molecular
pathogenesis of the disease, particularly with regard to the chronic changes
in the axial skeleton.

A group of spondylitis researchers and experts in other relevant fields was
convened in September of 1998 to explore the new and emerging research
findings in spondylitis, identify research gaps and opportunities and foster
research collaborations.  A summary of the conference and research questions
raised can be found at:  (http://www.nih.gov/niams/reports/b27summ.htm)

The purpose of this announcement is to encourage pilot and developmental 
projects (R21) and investigator initiated research projects (R01) that explore
new approaches and hypotheses on the pathogenesis of AS and other
spondyloarthropathies. In addition, the initiative also seeks to promote the
development and pilot testing of new therapeutic approaches, including
alternative and complementary medicine. Potential areas of research include,
but are not limited to:

development and assessment of new imaging methodologies, such as CT, MRI, 
ultrasound, and bone densitometry, for early and accurate diagnosis of AS and 
for detecting responses to new therapies; and development and assessment of 
image-guided treatments;

studies on the genetics of spondyloarthropathies and on the interactions between 
genes and environmental factors that are involved in pathogenesis;

studies on mechanisms of disease immunopathogenesis in the human and in 
experimental systems, including the role of B27 subtypes, peptide binding 
specificity, and T cell recognition in AS;

studies on sacroiliac joint pathology and immunology in AS;

studies to define the pathology and distribution of entheseal changes, the role 
of micro-organisms, immune cells, and HLA-B27 in AS;

studies on mechanisms of pathogenesis of psoriatic arthritis, inflammatory bowel 
disease, and reactive arthritis (Reiter's syndrome);

investigations on the role of intestinal microflora in local manifestations and 
systemic manifestations of disease;

studies on the molecular basis of organ involvement in HLA-B27-associated 
diseases; mechanisms of bone and cartilage injury in both axial and 
peripheral joints;

studies on mechanisms of ocular involvement in spondyloarthropathy including 
uveitis, iritis, and conjunctivitis;

development of novel therapeutic strategies and new in vivo and in vitro models 
for the evaluation of new therapies.

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 are 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
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.

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

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 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 the 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:
(http://grants.nih.gov/grants/guide/notice-files/not98-024.html).

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

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 2, 2001, 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 this RFA. Although a letter of intent is not required, is not binding, does
not commit the sender to submit an application, and does not enter into the
review of a subsequent application, the information that it contains allows IC
staff to estimate the potential review workload and plan the review. The
letter of intent is to be sent (e-mail, fax or post) to Dr. Tommy Broadwater
at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach.  The
just-in-time concept allows applicants to submit certain information only when
there is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions. The total direct costs must be requested in
accordance with the  program guidelines and  the modifications made to the
standard PHS 398 application  instructions described below:

PHS 398

FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative  (F&A) costs] for the initial budget 
period, and Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of 
the PHS 398. It is not required and will not be accepted with the application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. 
(See http://grants.nih.gov/grants/funding/modular/modular.htm  for sample
pages.) At the top of the page, enter the total direct costs requested for each 
year.  This is not a Form page.

Under Personnel, list all project personnel, including their names, percent of 
effort, and roles on the project. No individual salary information should be 
provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of all personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount.  Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:
(http://grants.nih.gov/grants/funding/modular/modular.htm).

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

RESEARCH PLAN - The research plan (a-d) is limited to 25 pages for R01s and 10
pages for R21 applications. Applications that exceed the page limit will be
returned without review. An appendix may be included in the application;
however, the appendix is not to be used to circumvent the page limit of the
research plan.

CHECKLIST - This page should be completed and submitted with the application.
If the facilities and administration (F&A) rate agreement has been
established, indicate the type of agreement and the date. All appropriate
exclusions must be applied in the calculation of the F&A costs for the initial
budget period and all future budget years.

The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review. 

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98). These forms 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 301/435-0714, email: grantsinfo@nih.gov; and on the
internet at http://grants.nih.gov/grants/funding/phs398/phs398.html

For purposes of identification and processing, item 2a on the face page of the
application must be marked "YES" and the RFA number "AR-00-008" and the words
"SPONDYLOARTHROPATHIES: NEW APPROACHES TO PATHOGENESIS" must be entered on the
face page.

The RFA label and line 2 of the application should both indicate the RFA
number.  The RFA label must be affixed to the bottom of the face page. 
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.

The sample RFA label available at:
(http://grants.nih.gov/grants/funding/phs398/label-bk.pdf) has been modified
to allow for this change.  Please note this is in pdf format.

Applications must be received by March 13, 2001. Applications not received as
a single package on the receipt date or not conforming to the instructions
contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and
superseded by, the special instructions below, for the purposes of this RFA),
will be judged non-responsive and will be returned to the applicant.

If the application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but that has
not yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical applications
be reviewed by different review committees.  Therefore, an application that is
essentially identical to one that has already been reviewed cannot be
submitted in response to this RFA.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, including the
checklist, and three signed, exact, single-sided 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 mail or courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent to Dr.
Tommy Broadwater at the address listed under INQUIRIES.

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 should be included with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review and for responsiveness by NIAMS and NEI.  staff; those
judged to be incomplete or not in the format specified in this RFA will be
returned to the applicant without review. Those considered to be
non-responsive will be returned without review.

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 with the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in
which all applications will receive a written critique but only those
applications deemed to have the highest scientific merit will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory Councils of the NIAMS and NEI.

Review Criteria

The five criteria to be used in the evaluation of grant applications are
listed below.  To put those criteria in context, the following information is
contained in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques 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 by the reviewers 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 a 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 field?

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 method? 
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:

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.

The reasonableness of the proposed budget and duration in relation to the 
proposed research

The adequacy of the proposed protection for humans, animals or the environment, 
to the extent they may be adversely affected by the project proposed in 
the application

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort. The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims. For modular grant
applications, any budgetary adjustments recommended by the reviewers will be
in $25,000 modules. The duration of support will be reviewed to determine if
it is appropriate to ensure successful completion of the requested scope of
the project.

AWARD CRITERIA

Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities

INQUIRIES

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:

Bernadette Tyree, Ph.D.
Cartilage and Connective Tissue Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Bldg. Rm. 5A37
Bethesda Md 20892-6500
Telephone: (301) 594-5032
FAX: (301) 480-4543
Email: bt16w@nih.gov

Donald F. Everett
Collaborative Clinical Reseach Program
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd., MSC 7164
Bethesda, MD 20892-7164
Telephone: (301) 496-5983
FAX: (301) 402-0528
Email: dfe@eps.nei.nih.gov

Direct review inquiries to:

Tommy Broadwater, Ph.D.
Review Branch 
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Bldg. Rm. 5A25U
Bethesda, MD 20892-6500
Telephone: (301) 594-4953
FAX (301) 480-4543 
Email: broadwatert@mail.nih.gov

Direct inquiries regarding fiscal matters to:

Melinda Nelson
Grants Management Officer
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Bldg. Rm. 5A49F
Bethesda Md 20892-6500
Telephone: (301) 594-3535
FAX (301) 480-5450
Email: nelsonm@mail.nih.gov

Schedule:

Letter of Intent Receipt Date:    January 2, 2001
Application Receipt Date:         March 13, 2001
Peer Review Date:                 June, 2001
Council Review:                   September 24, 2001
Earliest Anticipated Start Date:  September 30, 2001    

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.846, Arthritis, Musculoskeletal and Skin Diseases Research.  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 intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.

The Public Health Service 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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