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Full Text PA-96-022
NIH GUIDE, Volume 25, Number 3, February 9, 1996
PA NUMBER:  PA-96-022
P.T. 34

  Disease Model 

National Institute on Aging
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental Research
National Institute of Diabetes and Digestive and Kidney Diseases
The National Institute on Aging (NIA), the National Institute of
Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National
Institute of Dental Research (NIDR) and the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) invite research
grant applications to develop or refine models and markers using
human bone, bone marrow or bone cell constituents which more
accurately reflect those age-related and/or pathophysiological
processes occurring within the mature human skeleton that lead to
osteoporosis and other age-related skeletal diseases. It is expected
that improved human models and markers of age-related changes in
skeletal tissue structure and function will enhance the accuracy and
reliability of diagnostic and prognostic capabilities and serve to
expedite the development of more effective, targeted preventive and
therapeutic strategies.
Model development and refinement should be conducted from the
perspective of facilitating a) the identification of better
prognostic indicators of the occurrence, progression, cessation or
reversal of skeletal involution (due to aging, menopause, age-
related morbidity, drugs); b) the identification of age-related
pathologies/co-morbidities contributing to compromises in peripheral,
axial and craniofacial skeletal integrity; c) the prediction of
response or non-response to various therapeutic agents and/or d)
further epidemiologic studies of risk factors for age-related bone
disease and bone loss and fracture outcomes.
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 PA,
Human Models and Markers of Skeletal Aging is related to the priority
area of osteoporosis.  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).
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.
Applications may  be submitted by single institutions or by a
consortia of institutions.  Foreign institutions are not eligible for
First Independent Research and Support and Transition (FIRST) awards
(R29), but may submit applications for individual research project
grants (R01): foreign applicants may also participate in laboratory
or clinical programs through subcontract or consortium arrangements.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
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.
This program announcement will use the NIH investigator-initiated
research project grant (R01) and FIRST (R29) award mechanisms. It is
anticipated that the size of an award will vary due to the nature and
scope of the proposed research, with the R01 award ranging from
$150,000 to $500,000 in total (direct plus indirect) costs per year.
Approximately $900,000 from NIA and up to $500,000 from NIAMS in
total costs for the first year of funding will be made available in
Fiscal Year 1997 to specifically fund applications submitted in
response to this PA for the February/March 1996, June/July 1996 and
October/November 1996 application receipt deadlines.  An additional
$300,000 from NIA and $200,000 from NIAMS will be made available in
Fiscal Year 1998 to fund applications for this PA which are submitted
by the February/March 1997 deadline.  NIDR maintains a special
interest in research focused on oral/craniofacial hard tissues,
including related model systems and intends to fund 2-4 additional
high quality applications in FY 1997.  NIDDK also maintains an active
interest in research questions related to the hormonal regulation of
bone in health and disease and anticipates funding of 2-3 additional
applications as funds warrant in FY97.  This funding level is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the NIA, NIAMS, NIDR and NIDDK, the award of
grants pursuant to this PA is contingent upon the availability of
funds at the time the awards are made.
Our ability to predict, prevent, slow or reverse age-related bone
loss and bone diseases such as osteoporosis is limited because so few
studies have focused on cells and skeletal tissue from the aging
human skeleton.  Although osteoporosis and age-related diseases such
as Paget's disease occur primarily in the mature, aging human
skeleton, in vitro models used to study bone biology have consisted
primarily of transformed cell lines from human or rodent
osteosarcomas, or cell systems derived from fetal or neonatal rodent
bone.  In addition to marked differences in the chemical composition
and macro- and microarchitectural organization of bone, other
anomalies imposed by current models that reflect inappropriate age,
species and other phenotypic characteristics limit the
generalizability of putative biological mechanisms to those occurring
in the human skeleton.
Appropriate model systems are needed to develop markers that are more
sensitive and specific in predicting changes in bone mass, bone
competence and fracture susceptibility.  Significant improvements in
techniques to assess the status of bone cell activity in the skeleton
are necessary to provide answers to key clinical questions such as 1)
is a given individual currently losing bone?, 2) by which mechanisms
is bone being lost?  3) at what anatomic site/compartment(s) is bone
being lost?, 4) at what rate is bone being lost?, 5) is a promising
new treatment likely to be effective, and if so, for which patients
and 6) if a treatment is initially effective, for how long will it
continue to be effective?
Models and markers which better reflect the proliferative capability,
differentiated function and qualitative features of bone cells in the
mature human skeleton will facilitate improved techniques to assess
the cellular and metabolic status of skeletal tissue.  Such advances
will further enhance the accuracy of diagnoses, prognoses and
decision-making with respect to available and future treatment
options and also facilitate the evaluation and targeting of potential
new therapies (based on an understanding of how responses to these
therapies are modified by age, gender, genetics and ethnicity).  The
acceleration of advances in bone biology and related fields as well
as the development of many new promising technologies (such as
transgenic animal models, in situ hybridization, immunocytochemistry
and reverse transcriptase polymerase chain reaction (RT-PCR) in
conjunction with histomorphometric, densitometric, qualitative, etc.
techniques) provide improved capabilities to address these problems.
A Workshop on Human Models of Skeletal Aging was organized and
sponsored by the NIA and the NIDR in Washington, D.C., on March 1-2,
1994.  Its objective was to address methodological issues integral to
facilitating clinically relevant studies on the causes and
consequences of bone loss and osteoporosis at the cellular and tissue
levels in the aging human skeleton.  The proceedings of this Workshop
have been published [Calcif Tissue Int (1995) 56(Suppl 1); pp S1-S56;
eds., Gehron Robey P and Sherman S].
Research Goals and Scope
The purpose of this initiative is to stimulate studies to develop or
refine and validate models and markers which more accurately reflect
processes mediating aging or age-related skeletal diseases of the
axial, peripheral and craniofacial skeleton, such as osteoporosis.
Research applications submitted in response to this PA must combine
all three of the following components in the research plan proposed
for the project period of the application (maximum five years):
1.  Development of model systems for human skeletal aging and
age-related disease, using human bone, bone marrow or other bone cell
2.  Use of these model systems to define new markers for diagnosis
and/or prognosis of age-related physiologic and pathologic changes,
and/or prediction of responsiveness to specific therapies AND,
3.  Validation of these models and markers against in vivo parameters
of skeletal status such as changes in bone mass, bone strength,
architecture, histomorphometric indices of bone turnover, or the
occurrence of fractures.
The validation of models and markers against in vivo parameters of
skeletal status is a required component for projects submitted in
response to this PA.  The validation component must include a plan to
determine the extent to which proposed models and markers reflect
changes due to age and/or age-related skeletal disease. Validation of
markers should also include an assessment of their sensitivity,
specificity, intra- and inter-individual variability (including
effects of age, gender, and ethnicity).
Types of models and markers that might be developed include, but are
not limited to:
o  Models of mature osteoblast, osteoclast, osteocyte, and bone
lining cell function
o  Models of osteoprogenitor cell recruitment, proliferation,
differentiation and function o  Validated peripheral blood cell
models (e.g. monocytes, CD 34+ cells) of osteoclast or
osteoclast-like function
o  Markers of bone cell phenotype and stage of differentiation
o  Models that reflect embryonic origin (e.g., neuroectoderm versus
o  Models using bone from multiple anatomic (peripheral, axial and
craniofacial) sites, and different types of bone, bone matrix, bone
marrow and other cellular constituents; development of techniques
requiring minimal amounts of skeletal material or constituents
o  Models derived from or synthesizing lamellar bone (of cortical or
trabecular origin)
o  Models that can reconstitute the "BMU" (basic multicellular unit)
which contains osteocytes, lining cells, osteoblasts, osteoclasts,
vascular components, etc.
In vivo parameters that could be used to validate these models and
markers include but are not limited to:
o  In vivo responses of bone (changes in bone mass, strength, etc) to
regulatory factors (hormones, cytokines, etc.) and pharmacologic
agents (measured by existing or new imaging techniques)
o  Bone cell or bone marrow progenitor proliferative capacity,
morphology, surface markers, gene expression, and/or expression of
differentiated function
o  Rates of bone formation and bone resorption (e.g., using
histomorphometric techniques)
o  In vivo/in vitro or in situ spatial organization of cells and
temporal sequence of events during the bone remodelling process
o  Qualitative and quantitative changes in organic and inorganic
skeletal tissue components (structure, extent of mineralization,
Because age-related bone loss and osteoporosis are heterogeneous and
multifactorial in nature, applicants are encouraged to adopt
interdisciplinary approaches, establishing or strengthening
interactions and integration of efforts between clinical and basic
science investigators.  Research teams should include, where
possible, a diverse range of expertise in areas such as bone biology,
molecular biology, bone densitometry, orthopedics, histomorphometry,
endocrinology, geriatrics, epidemiology and biostatistics.
Because the current state of knowledge on skeletal aging and
therapeutics in men is extremely limited, research proposing to
include men (as well as women) as participants is strongly
In their application(s), applicants are encouraged to request funds
for one to two participants to meet annually in Bethesda, Maryland
with investigators of similar projects.  Program directors from
participating institutes will coordinate these meetings which will
provide the opportunity for principal investigators to share
findings, discuss their work in progress and to raise cross-cutting
methodological and scientific issues.
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 is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
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 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
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.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Applications kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email:  girg@drgpo.drg.nih.gov.  The title and number
of this program announcement must be typed in Section 2 on the face
page of the application.
Applications for the FIRST (R29) award must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST (R29) award applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
The completed original application and five legible copies must be
sent or delivered to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer 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.
The review criteria to be used in the evaluation of applications
submitted in response to this program announcement are:
o  Scientific, technical, or medical significance and originality of
proposed research;
o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  Inclusion of all three required research components described
under Research Goals and Scope
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 the resources necessary to perform the research;
o  Appropriateness of the proposed budget and duration in relation to
the proposed research;
o  Adequacy of the provisions for the protection human subjects and
safety of the research environment; and
o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
Applications will compete for available funds with all other approved
applications assigned to that IC.  The following 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 priority.
Inquiries concerning this PA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Sherry Sherman, Ph.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 3E327
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1033
FAX:  (301) 402-1784
Email: ShermanS@gw.nia.nih.gov
Joan A. McGowan, Ph.D.
Bone Diseases Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-43E
45 Center Drive, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  mcgowanj@ep.niams.nih.gov
Joseph E. Ciardi, Ph.D.
Craniofacial Development and Disorders Program
National Institute of Dental Research
Natcher Building, Room 4AN-24E
45 Center Drive, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2337
FAX:  (301) 480-8318
EMail:  ciardiJ@de45.nidr.nih.gov
Ronald Margolis, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN-12J, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email:  rm76f@nih.gov
Direct inquiries regarding fiscal matters to:
Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: EllisJ@gw.nia.nih.gov
Ms. Vicki Maurer
Grants Management Office
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-49A
45 Center Drive, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3504
FAX:  (301) 480-5450
Email:  maurerv@ep.niams.nih.gov
Mr. Martin R. Rubinstein
Grants Management Office
National Institute of Dental Research
Natcher Building, room 4AN-44A
45 Center Drive MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8308
Email:  Martin.Rubinstein@NIH.GOV
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.866, 93.846, 93.847 and 93.121. 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 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 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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