BONE AND THE HEMATOPOIETIC AND IMMUNE SYSTEMS

Release Date:  April 13, 1999

PA NUMBER:  PA-99-085

P.T.

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging
National Institute of Dental and Craniofacial Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung, and Blood Institute

THIS PROGRAM ANNOUNCEMENT 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 ANNOUNCEMENT.

PURPOSE

The participating Institutes seek investigator-initiated projects that have the
potential to illuminate functional interactions between bone and the
hematopoietic and immune systems.  Recent observations underscore the linkage
between endochondral bone formation and the establishment of hematopoietic
marrow, and suggest that interactions between bone, marrow, and the immune system
persist in the mature skeleton.  Marrow stromal cells include the precursors of
the osteochondrogenic lineage, exert important influences on osteoclastogenesis
and lymphopoiesis, and mediate the effects of some systemic factors on bone
turnover.  Recent evidence indicates that hematopoietic cells can influence the
differentiation of osteogenic cells, and suggests that mature lymphocytes can
influence osteoclastic and osteoblastic functions.  In order to explore the
mechanisms that underlie these interactions, the participating Institutes will
support outstanding projects that have the potential to either clarify the
importance of specific cell types and effector molecules or identify previously
unrecognized cellular and molecular agents that influence bone physiology. 
Collaborations among bone biologists, hematologists, and immunologists, and
between basic scientists and clinical investigators, will be particularly
encouraged.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS led national
activity for setting priority areas. This Program Announcement, Bone and the
Hematopoietic and Immune Systems, is related to the priority area of Diabetes and
Chronic Disabling Conditions by virtue of its relevance to osteoporosis and other
conditions of bone loss and increased fracture risk. Potential applicants may
obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html

ELIGIBILITY REQUIREMENTS

Applications for research project (R01) support may be submitted by domestic and
foreign, for-profit and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.  Foreign
institutions are not eligible for program project (P01) grant support.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project grant
(R01) award and program project grant (P01) mechanisms.  Program project grants
may be effective mechanisms for facilitating interdisciplinary collaborations. 
However, policies on the acceptance and funding of program project applications
vary among the participating institutes.  Therefore, investigators are strongly
urged to contact appropriate institute staff before preparing P01 applications. 
Investigators may also wish to consider the Interactive Research Project Grant
mechanism (http://www.nih.gov/grants/guide/pa-files/PA-96-001.html) as a means
of coordinating related projects.  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 PA may not
exceed 5 years.

Specific application instructions have been modified to reflect "MODULAR GRANT"
and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  The modular
grant concept, which applies to R01 grant applications with total direct costs
not exceeding $250,000 per year, 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. 
Complete and detailed instructions and information on Modular Grants can be found
at  http://www.nih.gov/grants/funding/modular/modular.htm.  Highlights of the new
format are noted below.

o  Modular grant applications will request direct costs in $25,000 modules, up
to a total direct cost request of $250,000 per year.  A typical modular grant
application will request the same number of modules in each year.

o  Application budgets will be simplified.  Detailed categorical budget
information will not be submitted with the application; budget form pages of the
application kits will not be used.  Instead, total direct costs requested for
each year will be presented.  Information, in narrative form, will be provided
only for Personnel and, when applicable, for Consortium/Contractual Costs.  See
section on application instructions below.

o  Additional narrative budget justification will be required in the application
only if there is a variation in the number of modules requested.

o  There will be no routine escalation for future years.  In determining the
total for each budget year, applicants should first consider the direct cost of
the entire project period.  Well-justified modular increments or decrements in
the total direct costs for any year of the project that reflect substantial
changes in expected future activities may be requested.  For example, purchase
of major equipment in the first year may justify a higher overall budget in the
first, but not in succeeding years.

o  Other Support pages of the PHS 398 will not be submitted with the application.

o  Information on research projects ongoing or completed during the last three
years of the principal investigator and key personnel will be provided as part
of the "Biographical Sketch."  This information will include the specific aims,
overall goals and responsibilities and should include Federal and non-Federal
support.  This information will be used by reviewers in the assessment of each
individuals qualifications for a specific role in the proposed project.

o  Following peer review, information about Other Research Support will be
requested by NIH from the applicant for applications being considered for award.

o  Additional budget information will be requested only under special
circumstances.

RESEARCH OBJECTIVES

Background

The interdependence of bone and the hematopoietic system has long been apparent. 
In the higher vertebrates, development of bone marrow occurs in conjunction with
the process of endochondral bone formation.  During this process, establishment
of the marrow environment depends upon the excavation of hypertrophic cartilage
and bony trabeculae by osteoclasts, which arise from the hematopoietic monocyte-
macrophage lineage.  Marrow stromal cells include the progenitors of the
osteoblastic lineage and are the sources of effector molecules that support and
regulate both hematopoiesis and bone remodeling.  During remodeling of cancellous
bone, both osteoclasts and osteoblasts function in close apposition to
hematopoietic cells.  Yet much remains to be learned about the cellular and
molecular signaling pathways that operate between the many different cell types
present in the marrow.

Relationships between bone and the immune system are less obvious.  Osteopetrotic
syndromes, arising from deficiency of bone resorption, often include associated
immune defects.  However, this seems most often to be a secondary consequence of
the failure to establish a normal hematopoietic environment.  Glucocorticoids and
other immunosuppressant drugs are observed in the clinic to precipitate a net
loss of bone that can predispose to fracture.  Similarly, many cytokines and
other regulatory molecules that are important regulators of immune cell
differentiation and maturation also have potent effects on osteoblasts and
osteoclasts.  However, it is for the most part unclear whether these parallels
reflect interaction between bone cells and immune cells, or instead, independent
effects of the agents.

The scientific workshop "Bone and the Hematopoietic and Immune Systems" was
convened in August, 1997 by the National Institutes of Health to discuss recent
work in this area and to identify new areas of research.  A summary of the
proceedings has been published in the Journal of Bone and Mineral Research
(Sharrock WJ. J Bone Miner Res, 1998:13:537-543).

Research Objectives and Scope

Appreciation of the complexity of the factors that may influence bone is still
growing.  Clearly, many potentially interacting cell types and participating
effector molecules must be considered in interpreting laboratory results and
clinical observations.  Future efforts seem likely to be particularly rewarding
if they can either clarify the importance of specific cell types and effector
molecules or identify previously unrecognized cellular and molecular agents that
influence bone physiology.  Important areas include, but are not limited to:

o  Determination of the mechanisms that regulate the differentiation of the
stromal, osteoblastic, and osteoclastic lineages, including the nature of
osteogenic stem cells and factors that govern the disposition of multipotential
precursors among alternate pathways;

o  Identification of other marrow cell types, such as  hematopoietic cells and
stages of lymphoid and myeloid differentiation, that may influence bone cells;

o  Characterization of functional interactions between cell types present in the
marrow;

o  Definition of homing of stem cells and hematopoietic precursors as a function
of stromal and matrix environments;

o  Exploration of the possibility that cells of the stromal/osteogenic lineage
circulate in the blood;

o  Determination of the mechanisms that underlie the organization of the marrow,
including specific cell-cell associations and the role of extracellular matrix
components;

o  Testing of the significance of hematopoietic and immune influences in the
differentiation of intramembranous as opposed to endochondral bone;

o  Definition of the differences between currently used model systems, with
attention to species and strain differences, properties of cells from different
anatomical sites, and the characteristics of different in vitro systems;

o  Determination of the mechanisms underlying the skeletal effects of systemic
factors, including sex steroids, PTH, and immunosuppressants, in terms of the
roles of intermediary cells and signaling pathways;

o  Testing of the possible roles of circulating lymphocytes and other immune
cells in normal and pathological bone metabolism;

o  Elucidation of the effect of osteopenia on hematopoiesis and of hematopoiesis
on bone elements in normal and pathological states, such as myelodysplasia and
aplastic anemia;

o  Study of the relationship between hematopoietic malignancies, such as myeloma,
and pathological bone resorption;

o  Determination of the mechanisms through which these complex molecular and
cellular interactions may be involved in bone loss in older subjects.

Collaborations among bone biologists, hematologists, and immunologists are
encouraged, as they can be expected to enrich the available array of models and
experimental systems.  For example, many transgenic and knockout mouse strains
have been developed to probe hematopoietic and immune regulatory mechanisms.  In
some cases, the phenotypes include well-defined changes in the numbers of
specific cell types and levels of regulatory molecules that may have important
effects on bone.  Examination of skeletal status in these strains may be
illuminating.  It is also anticipated that the utilization of technology allowing
cell type-specific gene inactivation and transgene expression should provide more
narrowly focused probes of mechanisms affecting bone.  Similarly, new in vitro
systems may provide opportunities to test interactions in complex populations of
cells.

Finally, because of the evident differences between humans and animals in several
important areas, the coupling of cellular and molecular analyses with clinical
observation and intervention is likely to be critical for future progress. 
Results from studies of the mechanisms of immunosuppressive drugs and the effects
of genetic disorders suggest that human pathology can provide important clues to
fundamental mechanisms.  There may be gains to be realized from examining the
skeleton in clinical situations in which disruptions of hematopoietic or immune
functions exist.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994 available on the web at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

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://www.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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted for the standard application receipt dates, as
indicated in the application kit. Application kits are available at most
institutional offices of sponsored research. Forms may also be obtained 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 ), or at
http://www.nih.gov/grants/funding/phs398/phs398.html .

For research project (R01) grants with total direct costs not exceeding $250,000
per year, the modifications noted below are to be used with application form PHS
398 (rev. 4/98).

BUDGET INSTRUCTIONS

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 - Use a Modular Grant Budget Narrative page.
(See http://www.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.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should be
provided.

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 key 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.

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://www.nih.gov/grants/funding/modular/modular.htm

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

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. It is important to identify all exclusions that were used 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.

Any applicant planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more in
direct costs for any year is advised that he or she must contact the Institute
or Center (IC) program staff before submitting the application, i.e., as plans
for the study are being developed. Furthermore, the applicant must obtain
agreement from the IC staff that the IC will accept the application for
consideration for award.  Finally, the applicant must identify, in a cover letter
sent with the application, the staff member and Institute or Center who agreed
to accept assignment of the application. This policy requires an applicant to
obtain agreement for acceptance of both any such application and any such
subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20,
1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html.

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

Submit a signed, typewritten original of the application, including the
Checklist, and five 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical merit by
an appropriate scientific review group convened in accordance with the standard
NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory council or
board.

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.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

AWARD CRITERIA

In addition to the participating Institutes, several other Institutes and Centers
have interests that are relevant to this Announcement.  Applications will be
assigned for possible funding according to existing referral guidelines and will
compete for available funds with all other approved applications. The following
will be considered in making funding decisions: quality of the proposed project
as determined by peer review, availability of funds, and program priority.  If
considered for funding by the NIAMS, applications that are responsive to this
Program Announcement are candidates for discretionary funding, as described at
http://www.nih.gov/niams/grants/payline2.htm .

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or 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, Room 5AS-37A
Bethesda, MD  20892
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  ws19h@nih.gov

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  fb12a@nih.gov

Kenneth A. Gruber, Ph.D.
Chronic and Disabling Diseases Branch
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18C, MSC 6401
Bethesda, MD  20892-6401
Telephone:  (301) 584-4836
FAX:  (301) 480-8318
Email:  kenneth_gruber@nih.gov

David G. Badman, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13C, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  David_Badman@nih.gov

Charles M. Peterson, MD
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC #7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868
Email:  petersoc@gwgate.nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Vicki L. Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37H
Bethesda, MD  20892
Telephone:  (301) 594-3504
FAX:  (301) 480-4543
Email:  vm8j@nih.gov

Bob Pike
Grants Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  pikeb@exmur.nia.nih.gov

Bonnie Smith
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44 MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Bonnie.Smith@nih.gov

Aretina D. Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
FAX:  (301) 480-3504
Email:  PerryA@extra.niddk.nih.gov

Jane Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC #7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  davisj@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.846, 93.866, 93.121, 93.849, and 93.839.  Awards are made under authorization
of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.

The PHS 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, and 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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