NEW RESEARCH STRATEGIES IN OSTEOGENESIS IMPERFECTA

Release Date:  December 8, 2000

RFA:  AR-01-001

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
 (http://www.nih.gov/niams/)
National Institute on Aging (NIA)
 (http://www.nih.gov/nia/)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov/)

Letter of Intent Receipt Date:  February 14, 2001
Application Receipt Date:       March 14, 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/PA.

PURPOSE

This initiative is intended to stimulate and support new research projects
that have the potential to increase our understanding of skeletal pathology in
osteogenesis imperfecta (OI), and to lead to improved therapeutic approaches
to the disease.  In particular, it is intended that new studies should test
the importance of dysregulated bone remodeling in the pathogenesis of OI, with
a view to exploiting pharmacological therapies that may ameliorate the
consequences of the underlying genetic defects.  A second major goal is an
improved understanding of osteoprogenitor cell biology that will form the
basis for future therapeutic efforts employing genetic modification and
transplantation of such cells.

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 Request for Applications (RFA), New
Research Strategies in Osteogenesis Imperfecta, is related to the priority
areas of fetal, infant and child deaths, and developmental disabilities. 
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.

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.  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) Research Project
Grant (R01) award mechanism.  Only new (Type 1) applications will be accepted
for this initiative.  Competing continuation (Type 2) applications will not be
accepted.  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total project
period for an application submitted in response to this RFA may not exceed 5
years.  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.  The earliest anticipated award date is September 30, 2001.

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm

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.   In
such a case, a letter of agreement from either the GCRC 
program director or principal investigator should be included with the
application.

FUNDS AVAILABLE

The NIAMS intends to commit up to $1 million in FY 2001 to fund 3 to 5 new
grants in response to this RFA. In addition, the NIA and NICHD will consider
for funding those meritorious applications that are relevant to the
Institutes' respective missions.  An applicant may request a project period of
up to 5 years and a budget for direct costs of up to $250,000 per year.
Because the nature and scope of the research proposed may vary, it is
anticipated that the size of each award will also vary. Although the financial
plans of the participating Institutes provide support for this program, awards
pursuant to this RFA are contingent upon the availability of funds and the
receipt of a sufficient number of meritorious applications of interest to each
Institute. At this time, it is not known if this RFA will be reissued.

RESEARCH OBJECTIVES

Background

Osteogenesis imperfecta (OI) is a genetic disease of bone, caused by mutations
in a gene for type I collagen, the principal structural protein of bone. 
Depending on the specific mutation, the severity of the disease varies from a
mildly increased risk of fracture to perinatal lethality.  Severe non-lethal
forms cause significant disability, deformity, and chronic pain.  A true
"cure" of the disease would presumably require correction of the underlying
genetic defect.  In September of 1999,  the National Institute of Arthritis
and Musculoskeletal and Skin Diseases, the NIH Office of Rare Diseases, the
Osteogenesis Imperfecta Foundation, and the Children's Brittle Bone Foundation
co-sponsored a meeting of investigators and patient advocates to discuss the
implications of recent reports of therapeutic success in treating osteogenesis
imperfecta.  A report of this meeting is available at 
http://www.nih.gov/niams/reports/osteogenimperf.htm.

In one reported approach, children with OI were treated with pamidronate, a
drug from the bisphosphonate family.  Members of this drug group have proven
effective in preventing the bone loss and increased fracture risk that occurs
in women after menopause.  Investigators reported marked improvements in bone
mineral density, bone size, fracture incidence, mobility, and pain in children
treated with intravenous pamidronate.  Although such a pharmacological
approach fails to address the underlying cause of OI, the apparent efficacy of
the treatment warrants further investigation. In addition, the suggestion of a
significant therapeutic effect with administration of a bisphosphonate
underscores the gaps in our understanding of OI.  Bisphosphonates generally
have the effect of reducing rates of bone resorption, and hence, bone
turnover.  Many forms of OI are associated with elevated bone turnover rates,
leading to osteopenia.  But it remains unclear how much of the pathology of OI
is due to high-turnover osteopenia, and how much to intrinsic matrix defects
caused by the collagen mutations.  It may be that addressing metabolic
imbalances, presumably caused by abnormal bone matrix, can ameliorate many of
the consequences of the collagen mutations, even though the mutations remain. 

In the second reported approach, children with OI received bone marrow
transplants, in an effort to replace mutant bone cells (which arise from
precursors in the marrow) with normal cells.  Investigators reported that
allogeneic bone marrow transplantation in children with OI resulted in
increases in growth rate and total body bone mineral content, accompanied by
histologic changes indicative of new bone formation, and a decreased incidence
of fractures.  The inherent risks of the transplantation procedure argue for
caution in pursuing this approach.  In addition, low levels of donor cell
engraftment in such transplants indicate that much remains to be learned about
the biology of non-hematopoietic marrow stromal cells and osteogenic precursor
cells. Nevertheless, marrow transplantation, especially if followed by "boost"
transfers of non-hematopoietic marrow stromal cells from the same donor,
closely parallels the process that will ultimately be necessary to achieve
true gene therapy for OI.

Specific Objectives

This initiative will support biological studies in areas that have the
potential to illuminate the mechanisms of skeletal pathology in OI, to improve
existing therapeutic approaches, or to lead to new therapies.  Projects with
interdisciplinary character, such as collaborations between collagen matrix
biochemists and cell biologists, or collaborations between clinicians and
basic scientists, are encouraged.  Studies may make use of materials derived
from human subjects, including patients with OI.  However clinical trials are
not eligible for support under this initiative.  The following examples are
illustrative, and are not intended to exclude other types of work that address
the objectives stated above.

o  Studies of interactions between bone cells and bone matrix, including
signaling pathways that may operate between cells and components of the
matrix, and the consequences of collagen deficiency or structural alteration
of collagen for such signaling.

o  Studies of the structural and functional consequences of mutations in the
type I collagens, especially mutations known to be important in the
pathogenesis of OI.

o  Studies of pathogenic mechanisms and the action of bisphosphonates in
models of OI, such as transgenic mouse strains expressing mutant type I
collagens.

o  Studies of the mechanisms determining the commitment of pluripotent
precursors to the osteogenic pathway, survival of osteogenic cells, and
engraftment of transplanted cells in the bone environment, as these processes
apply to therapeutic cell transplantation.

o  Development and improvement of techniques for the genetic modification of
cells in the osteogenic lineage, including strategies for blocking the
expression of dominant-negative gene products.

o  Studies of the effects of genetic mosaicism for OI-causing mutations.

o  Studies on the effects of aging on bone formation and remodeling in
osteogenesis imperfecta, including the effects of aging on bone precursor
cells.


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 sub-populations 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 indicating 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.

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 February 14, 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 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 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 research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants, with the modifications noted below. These forms are
available at most institutional offices of sponsored research and 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. 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. 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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.  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

o 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 Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o 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.

o 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.

o 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.

o 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.

o 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;

o CHECKLIST - This page should be completed and submitted with the
application. If the 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.

o 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. 

The RFA title and number must be typed on line 2 of the face page of the
application form and the YES box must be marked.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  Type the RFA
number on the label.  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. 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.  

Submit a signed, typewritten original of the application, including the
Checklist, and three signed 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/courier service)

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

Applications must be received by March 14, 2001.  If an application is
received after that date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) 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
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 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 the CSR and
responsiveness by the NIAMS. If the application is not responsive to the RFA,
CSR staff may 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
the NIAMS in accordance with the review criteria stated below.  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 the applications under
review, will be discussed and assigned a priority score.  These applications
will also receive a second level review by the Advisory Councils of the
participating Institutes.

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 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:

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 duration in relation to the
proposed research.

o  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.

Schedule

Letter of Intent Receipt Date:    February 14, 2001
Application Receipt Date:         March 14, 2001
Peer Review Date:                 June-July, 2001
Council Review:                   September, 2001
Earliest Anticipated Start Date:  September 30, 2001

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 answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

William J. Sharrock, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Natcher Building, Room 5AS-37A
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX: 301-480-4543
Email: ws19h@nih.gov

Jill L. Carrington, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Gateway Building, Room2C231
Bethesda, MD   20892
Telephone: (301) 496-6402
FAX: 301-402-0010
Email: carringtonj@nia.nih.gov

Karen K. Winer, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6877
FAX:  (301) 480-9791
E-mail:  winerk@exchange.nih.gov

Direct inquiries regarding review issues 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. 5A49
Bethesda Md 20892-6500
Telephone: (301) 594-3535
FAX (301) 480-5450
Email: mn23z@nih.gov

Linda Whipp
Supervisory Grants Management Specialist
National Institute on Aging
7201 Wisconsin Avenue, Gateway Building, Room2N212
Bethesda, MD   20892
Telephone: (301) 496-1472
FAX (301) 402-3672
Email: lwl7m@nih.gov

Andrew Jones
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6995
FAX:  (301) 402-0915
E-mail:  jonesa@exchange.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.846, Arthritis, Musculoskeletal and Skin Diseases Research, No. 93.866,
Aging Research, and No. 93.865, Research for Mothers and Children.  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 PHS strongly encourages all grant 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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