RELEASE DATE:  August 12, 2004

PA NUMBER:   PA-04-139

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date. The 
non-AIDS portion of this funding opportunity expires on the date indicated below. 
A replacement R21 (PA-06-450) funding opportunity announcement has been issued 
for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute on Aging (NIA)
National Institute of Dental and Craniofacial Research (NIDCR)



o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


This announcement solicits proposals of research employing genetically 
defined and genetically modified mouse models to explore the biological 
mechanisms underlying non-inflammatory joint degeneration, or osteoarthritis.  
Inflammatory processes are evident in late stages of osteoarthritis, and are 
likely to be major contributors to the chronic pain that is the most common 
symptom of the condition.  However, for the purpose of this initiative, 
osteoarthritis is distinguished from diseases, such as rheumatoid arthritis, 
in which inflammation arising from autoimmunity is the primary cause of 
tissue damage. In contrast, the root causes of joint degeneration in 
osteoarthritis remain unclear. Increasing knowledge of molecular mechanisms 
in cartilage and bone biology, along with advances in the genetic 
manipulation of mice, have yielded new concepts and new animal models that 
may be relevant to osteoarthritis in humans. This Program Announcement is 
intended to accelerate the characterization of new models and the testing of 
hypotheses that could lead to improved diagnosis and treatment of 



Osteoarthritis is the most common form of arthritis and the major cause of 
activity limitation and physical disability in older people.  Current 
treatments for osteoarthritis are largely palliative, and many cases 
eventually require replacement of the joint with a prosthesis. Joint 
replacement is costly, and the finite functional life of prostheses can make 
a second replacement necessary, compounding the cost and risk for associated 
morbidity. Efforts to develop methods for the surgical or biological repair 
of damaged articular cartilage face major obstacles, owing to the limited 
intrinsic repair capacity of the tissue. Thus, much could be gained if the 
root causes of joint degeneration could be identified. Risk assessment or 
diagnosis at early stages of disease progression, coupled with the 
development of preventive or therapeutic interventions, could reduce health 
care costs and substantially improve the quality of life for older people. 
The development of preventive strategies and early-stage interventions for 
osteoarthritis is likely to depend upon the identification of the molecular 
and cellular mechanisms that underlie progressive deterioration of joint 
structure and function.

Osteoarthritis is characterized by degeneration of the articular cartilage 
surfaces of a joint. Within the cartilage environment, this degeneration is 
reflected in the functional decline and apoptosis of chondrocytes, and by 
elevated levels of proteases known to participate in the breakdown of 
extracellular matrix. The development of osteoarthritis is strongly 
correlated with age. Yet there is evidence that joint degeneration is not an 
inevitable consequence of aging, and that the factors influencing joint 
structure and function are complex. The knee and hip are more often affected 
than other joints, and one hip or knee may be more seriously affected than 
the other in the same individual. Genetic factors may predispose some 
individuals to develop osteoarthritis. The mechanical history of a joint, 
including both normal patterns of use and traumatic injury, is likely to be a 
major factor.

Recent observations suggest that it may be helpful to consider the joint as 
an integrated structure of bone and cartilage. During skeletal development, 
the hypertrophic chondrocytes of growth plates normally undergo apoptosis, 
and cartilage is degraded and replaced by bone. In the regions that will 
become the articular surfaces of joints, cartilage is retained over a 
supporting region of subchondral bone. One current hypothesis is that 
osteoarthritis reflects the inappropriate recurrence of the hypertrophic 
pathway in articular chondrocytes. The formation of bony outgrowths, or 
osteophytes, in osteoarthritic joints is consistent with this idea. If this 
hypothesis is sound, it follows that osteoarthritis may arise in part from 
disruption of mechanisms that establish and maintain the boundary between 
articular cartilage and subchondral bone. Thus, at least some of the causes 
of osteoarthritis may lie within the complex network of mechanisms that 
regulate the development and growth of the skeleton early in life.

The development of powerful methods for the genetic manipulation of mice has 
led to the creation of modified strains in which the consequences of specific 
genetic characteristics can be assessed in the intact animal and across the 
lifespan. In some instances, it has been reported that specific gene 
inactivation or over-expression results in age-related joint degeneration, 
with histological similarities to osteoarthritis. Several inbred mouse 
strains have also been observed to develop osteoarthritis-like joint 
degeneration with age. Because both genetic and environmental factors may be 
precisely defined in the laboratory, these mouse models hold the potential to 
reveal the genetic factors and hence the molecular pathways that influence 
the degeneration of joints.  


This program will support research with the potential to reveal the 
biological mechanisms underlying non-inflammatory joint degeneration in mouse 
models. Research supported by this initiative will identify specific genes, 
proteins, and biochemical pathways that contribute to joint degeneration. 
Information to be gained will include the timing and anatomical location of 
events that lead to joint degeneration, the functional characterization of 
proteins identified as causal factors, and the definition of pathways by 
which particular gene products contribute to joint degeneration. Objectives 
include: the characterization of new models; the development and testing of 
hypotheses that arise from the properties of new and existing models; and the 
definition of functional roles for specific molecular entities identified as 
contributing to joint degeneration. 

The NIDCR is interested in supporting meritorious research targeting new 
animal models of osteoarthritis that have relevance to the temporomandibular 
joint (TMJ). Applications describing animal models that elucidate molecular 
mechanisms of TMJ degeneration and aid in the diagnosis and treatment of TMJ 
Disorders are particularly encouraged. Applications addressing unique 
features of the TMJ including the presence of fibrocartilage on its 
articulating surfaces and the distinctive anatomy and mechanical loading of 
this joint also are of interest to the NIDCR.
Suggested research topics may include, but are not limited to:

o Molecular characterization of phenotypes of mice exhibiting joint 
degeneration, for example, by correlating gene expression profiles with time 
of onset, rate of progression, and severity;

o Identification of downstream effectors in pathways mediating effects of 
gene inactivation or transgene expression in genetically modified mice 
exhibiting joint degeneration;

o Mapping of genetic loci linked to joint degeneration in inbred mouse 

o Characterization of changes at the chondro-osseous junction that precede or 
accompany degradation of the articular surface in mouse models; or

o Testing of models of joint degeneration by specific antagonism of 
biological functions, using anti-sense, dominant-negative, or RNAi 


This PA will use the NIH R01 and Exploratory/Developmental Research 
Grant (R21) award mechanisms 
(  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project.  Applications using the R21 mechanism may 
request a project period of up to two years with a combined budget for direct 
costs of up $275,000 for the two year period, excluding the facilities and 
administrative (F&A) costs requested by consortium participants.  For example, 
the applicant may request $100,000 in the first year and $175,000 in the 
second year.  The request should be tailored to the needs of the project.  
Normally, no more than $200,000 may be requested in any single year.

This PA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at  


You may submit (an) application(s) if your institution has any of the 
following characteristics: 
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations


Individuals with the skills, knowledge, and resources necessary to carry out 
the proposed research are invited to work with their institution to develop 
an application for support.  Individuals from underrepresented racial and 
ethnic groups as well as individuals with disabilities are always encouraged 
to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas: scientific/research; and financial or grants management issues.

o Direct your questions about scientific/research issues to:

William J. Sharrock, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD  20892-4872
Telephone:  (301) 594-5055
FAX:  (301) 480-4543

Jill L. Carrington
Musculoskeletal Biology Program
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD   20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010

John W. Kusiak, Ph.D.
Molecular and Cellular Neurobiology Program
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Natcher, Building 45, Room 4AN-18A
Bethesda, MD 20892-6402
Telephone: 301-594-7984
FAX: 301-480-8319
o Direct your questions about financial or grants management matters to:

Michael G. Morse
Deputy Chief, Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
One Democracy Plaza
6701 Democracy Blvd., Suite 800
Bethesda, MD  20892-4872
Phone:  (301)594-3506

Ms. Linda Whipp
Grants and contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212
Bethesda, MD   20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672

Mary Daley
Chief Grants Management Officer
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Natcher, Building 45, Room 4AN-44B
Bethesda, MD  20892-6402
Telephone: 301-594-4808
FAX: 301-480-3562


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The D&B number can be obtained by calling (866) 705-5711 or 
through the web site at The D&B number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at  Application 
deadlines are also indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of the NIH 
institutes or centers who has agreed to accept assignment of the application.

The NIAMS imposes specific requirements on the submission of applications 
requesting $500,000 or more per year, superseding the NIH-wide requirements 
described below.  The NIAMS requirements are described in detail at and at  Briefly, applications 
are considered only for the June 1/July 1 (Cycle II) and October 1/November 1 
(Cycle III) receipt dates.  A potential applicant must seek NIAMS acceptance 
of such an application no later than March 1, for a June 1/July 1 submission, 
and no later than July 1, for an October 1/November 1 submission.

Applicants requesting more than $500,000 per year from other institutes or 
centers (ICs) must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your         
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member       
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

SENDING AN APPLICATION TO THE NIH: 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)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at  The 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 a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by an appropriate national advisory council 
or board  


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 evaluate application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
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 

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).

plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  


Sharing Research Data 

Applicants requesting $500,000 or more in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, 
reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score. 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research will be assessed.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(, as 
mandated by the Health Research Extension Act of 1985 
(, and the USDA 
Animal Welfare Regulations 
(, as applicable. 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
Investigators should seek guidance from their institutions on issues related 
to institutional policies and local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers will 
consider the data sharing plan but will not factor the plan into the 
determination of the scientific merit or the priority score.

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
a complete copy of the updated Guidelines is available at
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy 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 

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 is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information,” 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at

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.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

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