RECEPTORS AND SIGNALING IN BONE IN HEALTH AND DISEASE

Release Date:  December 2, 1999

PA NUMBER:  PA-00-017

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental and Craniofacial Research
National Institute on Aging
National Institute of Child Health and Human Development

THIS PA 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 PA.

This PA replaces DK-96-076, which was published in the NIH Guide, Vol. 25, 
No. 33, October 4, 1996.

PURPOSE

The objective of this initiative is to elicit grant submissions that focus on 
systemic hormones, local growth factors, and bone-active cytokines, their 
receptors and mechanisms of signaling in bone.  While the primary focus is on 
basic research, the long-term emphasis is on identifying mechanisms or 
processes related to hormone action with potential applicability as targets 
for therapeutic agents that may have efficacy in the treatment of diseases 
that adversely affect bone, such as osteoporosis and primary 
hyperparathyroidism.

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 PA, Receptors and 
Signaling in Bone in Health and Disease, fits the criteria of Chronic 
Disabling Diseases. Potential applicants may obtain a copy of "Healthy People 
2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000
 
ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
nonprofit 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 PA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  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.  
Complete and detailed instructions and information on Modular Grants can be 
found at http://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

Summary

The NIDDK, NIAMS, NIDCR, and NIA issued a Program Announcement on October 4, 
1996 entitled: “Anabolic Hormones in Bone: Basic Research and Therapeutic 
Potential.” The PA followed the recommendations for research initiatives from 
a workshop of the same title held May 1-2, 1995, organized by the NIDDK, and 
co-sponsored by the NIAMS and the NIH Office of Research on Women’s Health.  
Since that time considerable progress has been made in understanding the 
roles of hormones, growth factors, and cytokines in the regulation of bone.  
It is still clear, however, that diseases that affect bone, such as 
osteoporosis and primary hyperparathyroidism, result in gradual loss of bone 
and resulting osteopenia (thinning of the bones), a leading cause of 
fractures in adults.  Research has shown that this is particularly prevalent 
in postmenopausal women, though men are also susceptible to osteoporosis.  
Hormones are major regulators of bone mass and osteopenia may result from 
alterations in hormone action, such as loss of normal estrogen production in 
post-menopausal women, excessive production of parathyroid hormone (PTH) as 
in primary hyperparathyroidism, or glucocorticoid excess as a consequence of 
chronic steroid use in immunosuppressive therapy.  Moreover, defects in 
signaling during development can result in severe dysplasias in bone, such as 
Jansen’s dyschondroplasia, caused by aberrant PTHrP signaling.  Indeed, 
studies on bone morphogenesis have revealed roles for signaling through 
peptides such as sonic hedgehog, PTHrP, BMP, and hox gene products in bone 
cell fate determination, cell differentiation, and formation of mature bone.  
That cell signaling in developing and mature bone cells is key to maintaining 
proper mineral balances and peak bone mass was revealed through studies 
funded in response to the original PA and other recent initiatives.  Other 
imbalances in local growth factors and/or bone-active cytokines resulting 
from a variety of conditions may also contribute to osteopenia.  Limited 
clinical trials have determined that hormone replacement can partially 
mitigate or reverse the osteopenia associated with menopause, hypogonadism or 
primary hyperparathyroidism.  Use of estrogen/progesterone hormone 
replacement therapy (HRT) has gained wide acceptance in peri- and post-
menopausal women, though not without undesired side effects.  The development 
and use of Selective Estrogen Receptor Modulators (SERMs) has served to 
partially offset the side effects while giving some degree of protection 
against postmenopausal bone loss.  Still other therapeutic agents have been 
developed that alter mineral content and/or molecular structure of bone 
(e.g., bisphosphonates) or that alter hormonal balances (e.g., calcitonin, 
vitamin D).

While the primary focus is on basic research, the long-term emphasis should 
be on identifying mechanisms or processes associated with hormonal regulation 
of bone cell structure/function emphasizing signaling in bone cells and their 
precursors, with potential applicability as therapeutic agents for the 
treatment of diseases which adversely affect bone, including osteoporosis and 
primary hyperparathyroidism.
 
Research Objectives and Scope
 
The major areas of interest and potential that have been identified relevant 
to this program announcement are the following:
 
o The mechanism(s) of action of sex steroids, including estrogen, selective 
estrogen receptor modulators (SERMs), partial agonists, and agents with 
estrogen-like activity in bone; androgens and androgen-like agents which 
express positive, anabolic effects on bone.
 
o Other members of the nuclear hormone receptor superfamily, including PPAR, 
vitamin D, and others and their role(s) in signaling in bone cells and bone 
cell precursors.
 
o Parathyroid hormone (PTH) and/or parathyroid hormone-related peptide 
(PTHrP) and agonists or partial agonists which express PTH- or PTHrP-like 
anabolic effects in bone and the mechanisms of signaling in developing and 
mature bone.
 
o Insulin-like growth factor I (IGF-I), receptors, IGF-I binding proteins, or 
any other component of the IGF axis which signal in bone.
 
o Fibroblast growth factor(s) and their role(s) in bone/cartilage development 
and/or angiogenesis related to bone.
 
o Members of the Bone Morphogenetic Protein family (e.g., TGFs), and other 
cytokines (e.g., CSF-1), their receptors, and signaling pathways in bone.
 
o Novel transcription factors, such as osteoprotegrin, Cfba1, other hox gene 
products, and their mechanisms of signaling in bone cells and their 
precursors.
 
o Prostaglandins with effects on bone cells.
 
o Interleukins, including those that have positive effects and agents which 
can oppose putative negative effects on bone.

This is by no means a complete listing of potentially important hormones, 
growth factors, or cytokines.  The general focus should be on developing an 
understanding of the putative mechanism(s) of action of these agents with the 
goal of defining what aspect(s) of signaling in bone may be affected and how 
anabolic or other beneficial therapeutic actions may be achieved and 
sustained.  The NIDDK, NIAMS, and NIA share a mission to provide broad 
fundamental and clinical research support for a spectrum of chronic and 
disabling diseases that affect bone, including osteoporosis, and other forms 
of generalized bone loss. The NIDDK has a special interest in primary 
hyperparathyroidism and the mechanism of action of calciotropic hormones.  
The NIDCR has a special interest in research focusing on craniofacial bone.  
The NIA has a special interest in research that addresses changes in the 
levels of, and biologic responses to, bone regulatory factors as a 
consequence of aging.  

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 
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://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may also 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 at the standard application deadlines as indicated 
in the application kit.  Application kits are available at most institutional 
offices of sponsored research, or may 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.

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 program 
staff of the relevant Institute (listed at the end of this announcement) 
before submitting the application, i.e., as plans for the study are being 
developed.  Furthermore, the application must obtain agreement from the staff 
that the Institute 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 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://grants.nih.gov/grants/guide/notice-files/not98-030.html

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

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 key 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 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.  
Include the Letter of Intent to establish a consortium. Indirect costs for 
subcontracts are included in the total costs for the application. 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 program announcement title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.

Submit the signed, original, single-sided application, including the 
Checklist, along with five signed photocopies and five collated sets of 
appendix materials 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)

The Center for Scientific Review (CSR) will not accept any application in 
response to this PA 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

Applications will be assigned on the basis of established Public Health 
Service 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, reviewer 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.

o 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?

o 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?

o 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? 

o 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)?

o 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 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 to the proposed 
research.

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

o Availability of special opportunities for furthering research programs 
through the use of unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in the United 
States or which provide augmentation of existing U.S. resources.

AWARD CRITERIA

Applications will be assigned to Institutes for possible funding according to 
existing referral guidelines, and will compete for available funds with all 
other recommended applications assigned to the participating Institutes. The 
following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Ronald N. Margolis, Ph.D.
Senior Advisor, Molecular Endocrinology
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN-12J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email:  rm76f@nih.gov
 
William Sharrock, Ph.D.
Bone Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37A
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  ws19h@nih.gov
 
Dr. Kenneth A. Gruber
Chief, Chronic Diseases Branch
National Institute of Dental and Craniofacial Research
45 Center Drive
Bethesda, MD 20892
Tel.: 301-594-4836
Email: kenneth_gruber@nih.gov

Frank Bellino, PhD
Endocrinology Program Administrator
Biology of Aging Program
National Institute on Aging
Gateway Bldg., Suite 2C231
Bethesda, MD  20892-9205
phone: 301 496-6402
fax: 301 402-0010
Email:  bellinof@gw.nia.nih.gov

Karen Winer, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD 20892-7510
Phone:  301/435-6877
Fax:    301/480-9791
Email:  winerk@mail.nih.gov



Direct inquiries regarding fiscal and administrative matters to:
 
Kim Law
Grants Management Specialist
Building 45, Room 6AS-49A
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive
Bethesda, MD  20892-6600
Telephone:  (301) 594-8869
 
Vicki Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-37H
Bethesda, MD  20892-6500
Telephone:  (301) 594-3504
FAX:  (301) 480-4543
Email:  vicki_maurer@nih.gov
 
Martin R. Rubinstein
National Institute of Dental Research
45 Center Drive, Room 4AN44A
Bethesda, MD  20892-6402
Telephone  (301) 594-4800
FAX:  (301) 480-8301
E-mail:  Martin.Rubinstein@NIH.GOV
 
Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  28092-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  pikeb@gw.nia.nih.gov

E. Douglas Shawver
Grants Management Branch
NICHD
6100 Executive Blvd., Room 8A17
Bethesda, MD 20892-7510
Telephone: (301) 496-1303
FAX?301) 402-0915
E-mail: shawverd@hd01.nichd.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.847 (NIDDK), 93.846 (NIAMS), 93.121 (NIDCR), 93.866 (NIA) and 93.865 
(NICHD).  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 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 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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