DEVELOPMENT OF IN VITRO MODELS OF HUMAN ORAL MUCOSA RELEVANT TO AIDS 
AND MUCOSAL INFECTIONS  

RELEASE DATE:  October 31, 2003
 
RFA Number: RFA-DE-05-002 (This RFA has been reissued, see RFA-DE-06-003)

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION: 
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidcr.nih.gov)
 
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  
No. 93.121, Oral Diseases and Disorders Research
 
LETTER OF INTENT RECEIPT DATE:  July 28, 2004
APPLICATION RECEIPT DATE:  August 26, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of This RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The objective of this initiative is to stimulate research that will 
lead to the development and validation of a practical and 
physiologically relevant in vitro human model of the oral mucosa that 
can be used to study HIV infection and the complications associated 
with AIDS under highly controlled conditions.  It is envisioned that 
the availability of such an in vitro human oral mucosa system will 
provide opportunities to substantially enhance the fundamental 
understanding of oral HIV infections.  This will establish a scientific 
basis for exploring and testing diagnostic, treatment and prevention 
strategies for HIV infections and AIDS associated complications. Such 
models will be used to study, for example, the biology of viral (HIV, 
EBV, HHV-8, HPV) infection, pathogenesis of diseases, opportunistic 
complications and host defense immune responses.

RESEARCH OBJECTIVES

Background

Among the routes of transmission that HIV uses to infect the host is 
the oral mucosal tissue. This route of infection has been shown in both 
humans and primates.  HIV RNA and proteins can be detected directly in 
the mucosa, as well as in the saliva from infected subjects.  However, 
infectious HIV virions are rarely found in the saliva, suggesting that 
the oral mucosa is not permissive for efficient HIV replication. Our 
understanding of HIV pathogenesis is far from complete as is our 
understanding of how other opportunistic pathogens (HHV-8, CMV, EBV, 
HPV and Candida) infect and cause the oral complications associated 
with AIDS.  The ability of the oral cavity to resist HIV while 
providing a safe haven for other pathogens provides a unique 
opportunity to dissect the differential patterns of host defense or 
lack thereof.

The oral mucosa is composed of both stratified and non-stratified 
epithelial cells which form a continuously renewing, protective 100 um 
layer in the mouth.  The mucosa contains immunologically functional 
cells; including dendritic cells, lymphocytes, monocytes/macrophages 
and neutrophils; which increase markedly when the tissue is inflamed.   
Matrix components play a central role in maintaining the structure and 
function of an intact mucosa.  The surface of the mucosa is covered by 
salivary carbohydrates, lipids and proteins, and interacts directly 
with the oral environment, containing bacteria, fungi, viruses, food, 
tobacco products, alcohol etc. In addition, the mucosa produces or is 
bathed by cytokines, chemokines, antibodies and innate host factors in 
saliva. As such, these tissues are biologically complex and subject to 
numerous environmental and host factors that regulate their function 
and integrity.      

Compared with vaginal and rectal mucosa, research on oral mucosa has 
been aided by its relatively easy access.  However, research on oral 
mucosa, particularly in subjects with AIDS, has been very difficult 
because of the inability to control environmental influences, 
xerostomia, as well as site- and subject-specific immunological 
factors. Research on identifying protective or susceptibility factors 
in the oral mucosa in persons exposed to HIV would be greatly 
facilitated by the availability of high quality, standardized, and 
reproducible in vitro models of the mucosal tissue. Such models would 
lend themselves to advanced research in studying the genomics and 
proteomics of HIV infection and AIDS associated complications in the 
oral cavity. Moreover, due to the impossibility of using infectious 
virions in humans and the failure of animal models to recapitulate 
human infectious paradigms, the availability of an in vitro human model 
system is critical to advancing research on oral infection and/or 
identifying potential regulatory molecules which may provide insight 
into therapeutic targeting.  

Recent advances in tissue engineering and molecular and cellular 
biology have elucidated ways to construct tissues using carefully 
designed scaffolds on which cells can grow and differentiate. These 
bioengineered tissues can be manipulated to express phenotypic surface 
markers and to produce immune modulatory cytokines such as interleukin-
1, tumor necrosis factor and interleukin-8. While it may be feasible to 
construct a homogeneous epithelial model system, it becomes more of a 
challenge to develop a system in which stem cells, lymphocytes, 
epithelial cells, macrophages and dendritic cells, fibroblasts and 
keratinocytes, etc. can be incorporated to form a mucosal model.

Scope

The objective of this initiative is to encourage research that will 
lead to the development and validation of in vitro models of the human 
oral mucosa that are suitable for studying the pathogenesis of HIV and 
AIDS-related oral complications in a controlled environment. It is 
expected that investigators will capitalize on new findings in tissue 
engineering, cell biology of the oral mucosa, genomics, proteomics, 
bioimaging and real time analysis of gene expression. Multidisciplinary 
approaches and collaborations are encouraged. Examples of research 
topics that are responsive to this RFA are listed below but are by no 
means all inclusive:

Development of the models:

o Development of a model that can adequately address the effects of 
certain cells (e.g., neutrophils) and soluble factors (e.g., cytokines) 
on the oral mucosa.  Such cells and cytokines may be critical for viral 
adherence and internalization. 
o Utilization of 3D bioinductive scaffolds that can support growth of 
the cellular components and deliver essential growth factors.  
o Isolation, enrichment and characterization of epithelial basal layer 
stem cells required for maintaining long term survival of an in vitro 
oral mucosa.  Other somatic stem cells, such as mesenchymal or 
circulating hematopoietic stem cells, might also be evaluated.  
o Application of bioreactors designed to provide spatially uniform 
concentrations of cells within scaffolds;  control conditions in 
culture medium (e.g., temperature, pH, osmolarity, levels of oxygen, 
nutrients ); provide physiological relevant physical signals (e.g., 
interstitial fluid flow, shear, pressure, mechanical compression) 
needed to obtain long-term survival of the in vitro oral mucosa. 
o Establishment of the parameters under which optimal HIV 
infection/transcytosis of the mucosal epithelium occurs in the in vitro 
models.
o Determination of the optimal conditions for infection of the in vitro 
models with other relevant oral mucosal pathogens. 
o Utilization of a mucosal model to study the mechanisms by which 
pathogens that are associated with oral complications in HIV infection, 
such as EBV, HHV-8, HPV, CMV, HSV and Candida impact HIV permissiveness 
and vice versa.

Validation of the in vitro human models: 

o Use of sophisticated histological techniques and analysis of specific 
tissue markers to show that the in vitro oral mucosa is physiologically 
relevant to in vivo mucosa.
o Studies on transmembrane signaling pathways that are activated during 
HIV-host cell interaction.  
o Analysis of structural proteins involved in viral adsorption, 
internalization and endocytosis to cells in the model system.
o Identification or function of proteins and other molecules (e.g., 
lipids, mRNA) involved in cross talk between HIV infected and non-
infected host cells. 
o Comparison of gene expression in infected and uninfected oral mucosal 
tissues. 
o Gene and protein expression profiles of cells infected with orally-
relevant microbes and opportunistic pathogens (CMV, EBV, HPV etc.), 
prior to and during progression of simulated AIDS conditions; 
identification of factors which promote or inhibit the virus in this 
context.
o Analysis of the gene and protein expression profiles of HIV and host 
cells under quiescent and stress (pH, oxygen, heat) conditions.
o Gene and protein profiles of host leukocytes recruited to HIV 
infected oral mucosal tissues; use of laser confocal microscopy to 
identify and characterize infected cells.
o Studies on HIV inhibitory factors using in situ and real time 
techniques.  
o Development of assays applicable to the in vitro model for analyzing 
the effect of natural or pharmaceutical interventional agents.  
o Development and testing of potential agents that would impede, HIV 
and/or opportunistic oral pathogen amplification and dissemination 
within the mucosa.  

Applications using animal cells or tissue will not be responsive to 
this RFA. 

MECHANISM OF SUPPORT
 
This RFA will use NIH Individual Research Project Grant (R01) and the 
Exploratory/Development Research Grant (R21) award mechanisms.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  
Future unsolicited, competing-continuation applications based on this 
project will compete with all investigator-initiated applications and 
will be reviewed according to the customary peer review procedures.

This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.  
This program does not require cost sharing as defined in the current 
NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE 
 
The NIDCR intends to commit $2,000,000 total costs in FY 2005 to fund 6 
to 8 new and/or competitive continuation grants in response to this 
RFA. An R01 applicant may request a project period of up to 4 years and 
a budget for direct costs of up to $499,999 per year. An R21 applicant 
may request a project period of up to two years with a combined budget 
for direct costs of up to $275,000 for the two year period.  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 R21 cap may be exceeded by $25,000, direct 
costs per year to accommodate the facilities and administrative 
(indirect) costs associated with collaborative research at another 
institution. Because the nature and scope of the proposed research will 
vary from application to application, it is anticipated that the size 
and duration of each award will also vary. Although the financial plans 
of the NIDCR provide support for this program, awards pursuant to this 
RFA are contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications. At this time, it is not 
known if this RFA will be reissued.
 
ELIGIBLE INSTITUTIONS
 
You may submit 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
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is 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.   

SPECIAL REQUIREMENTS 
 
Grantees will meet annually at or near NIH, Bethesda, MD, to share 
results, to ensure that the NIDCR has a coherent view of the advances 
in the field, and to have an opportunity for collective problem solving 
among investigators.  Applicants should budget for travel in their 
requested budget for the principal investigator and one additional 
junior investigator to attend this annual meeting. 

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Mostafa Nokta, MD, PhD.
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial research
Building 45, Room 4AN-18H
45 Center Drive
Bethesda MD, 20892-6402
Telephone: (301) 594-7985
Fax (301) 480-8319
Email: Mostafa.Nokta@nih.gov
 
o Direct your questions about peer review issues to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44F
45 Center Drive
Bethesda, MD  20892-6402
Telephone:  (301) 594-2904
Fax:  (301) 480-8303
Email:  George.Hausch@nih.gov

o Direct your questions about financial or grants management matters 
to:

Mary Daley
Grants Management Branch  
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44B
45 Center Drive 
Bethesda, MD  20892-6402
Telephone: (301)-594-4808
Fax: (301)-480-3562
Email: md74u@nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows NIDCR staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to Dr. George 
Hausch at the address listed above.

SUBMITTING AN APPLICATION

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 DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 document is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

SUPPLEMENTARY INSTRUCTIONS FOR R21 APPLICATIONS:

All application instructions outlined in the PHS 398 application kit 
are to be followed with the following modifications for R21 
applications:

1. FACE PAGE, Item 6:  Up to a total of two years of support may be 
requested.  Total direct costs for the two years may not exceed 
$275,000.  

2. RESEARCH PLAN:  Items a-d may not exceed fifteen (15) pages, 
including tables and figures.  The following information should be 
taken into account for items a, b and c:  

o Item a, SPECIFIC AIMS--The instructions for this section suggest that 
the applicant state "the hypotheses to be tested".  Since some 
applications submitted in response to this RFA may also be design- or 
problem-driven (e.g., development of novel technologies), or need-
driven (initial research to develop a body of data upon which future 
research will build), hypothesis testing per se may not be the driving 
force in developing such a proposal and, therefore, may not be 
applicable.  The application should state the hypotheses, design, 
problem and/or need which will drive the proposed research.

o Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is 
important to identify clearly how the application addresses 
the specific objectives of this RFA and the purpose of the R21
mechanism.

o Item c, PRELIMINARY STUDIES/PROGRESS REPORT—No preliminary data are 
required for an R21 application.  

3.  APPENDIX.  Up to five articles may be submitted as appendix 
materials.  

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: (include if 
appropriate) Applications requesting up to $250,000 per year in direct 
costs must be submitted in a modular grant format.  The modular 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 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed original of the 
application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, send two additional copies of the 
application and all appendix material to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44F
45 Center Drive
Bethesda, MD  20892-6402
Telephone:  (301) 594-2904
FAX:  (301) 480-8303
Email:  George.Hausch@nih.gov

APPLICATION PROCESSING: Applications must be received on or before 
August 26, 2004.  If an application is received after that date, it 
will be returned to the applicant without review. 

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.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDCR. Incomplete and/or non-responsive 
applications will be returned to the applicant without further 
consideration. Applications that are complete and responsive to the RFA 
will be evaluated for scientific and technical merit by an appropriate 
peer review group convened by the NIDCR in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the NIDCR 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. The scientific review group will address and 
consider each of these criteria in assigning the application’s overall 
score, weighting them as appropriate for each application.   

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 forward.

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:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of 
human 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).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy 
of 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.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the 
sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to 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.  

ADDITIONAL REVIEW CONSIDERATIONS 

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

R21 APPLICATIONS:  The potential for ground-breaking, precedent-
setting research, with particular emphasis on novel and innovative 
approaches; and the potential to stimulate new concepts or approaches 
regarding important biomedical/behavioral problems, or provide a 
technique/system of wide applicability.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: July 28, 2004
Application Receipt Date: August 26, 2004
Peer Review Date: October 2004
Council Review: January/February 2005
Earliest Anticipated Start Date: February 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required 
for all types of clinical trials, including physiologic, toxicity, and 
dose-finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III).  The establishment of 
data and safety monitoring boards (DSMBs) is required for multi-site 
clinical trials involving interventions that entail potential risk to 
the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide 
for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
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 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: 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 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at http://stemcells.nih.gov/index.asp and 
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   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 review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The 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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  
The 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). 
Those who must comply with the Privacy Rule (classified under the Rule 
as “covered entities”) must do so by April 14, 2003 (with the exception 
of small health plans, which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) 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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ 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 http://grants.nih.gov/grants/policy/policy.htm 

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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