STEM CELLS IN DEVELOPMENT/REPAIR OF OROFACIAL STRUCTURES

RELEASE DATE:  February 5, 2002
 
RFA:  RFA-DE-02-006

PARTICIPATING INSTITUTES AND CENTERS (ICs):
 
National Institute of Dental and Craniofacial Research (NIDCR)
 (http://www.nidr.nih.gov/)
 
LETTER OF INTENT RECEIPT DATE:  March 18, 2002

APPLICATION RECEIPT DATE:  April 18, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the RFA
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

PURPOSE

The purpose of this RFA is to foster research on embryonic and adult 
stem cell biology that could facilitate the understanding of the 
complex events that occur during oral, dental, and craniofacial 
development.  It is envisioned that such knowledge will aid in the 
development of safe and effective stem cell-based treatments for the 
repair and regeneration of orofacial structures that have been 
compromised by congenital disorders, diseases, and injuries.

RESEARCH OBJECTIVES

Brief Background

Recent scientific discoveries concerning the ability of human embryonic 
stem cells (ES) to proliferate in an undifferentiated state and to be 
directed to develop into a wide array of cell types present 
opportunities for research that aim to repair or replace cells and 
restore vital functions. Exploration of these opportunities is now 
possible with the release of the NIH Guidelines for Human ES Cell 
Research and the availability of human cell lines through the NIH Human 
ES Cell Registry. 

Adult stem cells are present in many tissues of adult organisms and are 
important in tissue repair and homeostasis. These cells have the 
ability to self-renew (give rise to a replacement cell at each cell 
division with no apparent limitation) as well as generate another cell 
that is committed to differentiation in a particular tissue. 
Understanding the mechanisms of stem cell renewal could provide 
fundamental insights not only into the origin of multicellular 
organisms, but also into regeneration of specific tissues and 
elucidation of complex events such as tumorigenesis, whereby a "cancer 
stem cell" with a similar capacity for self-renewal drives disease progression. 

ES cells that are derived from embryos at the blastocyst stage may have 
a broader natural potential since, during development, they normally 
produce all the cells of an organism. These pluripotent cells are 
characterized by nearly an unlimited self-renewal and differentiation 
capacity which can give rise to many differentiated cell types 
including neurons, glia, skeletal myocytes, adipocytes and haemopoietic 
cells. The main difference between the embryo-derived pluripotent cells 
and the so-called multipotent adult stem cells is in the number of 
differentiated cell types that they can produce. This may reflect the 
different origins of these cells; pluripotent stem cells are derived 
from blastocyst cells, while adult stem cells are derived from somatic 
cells that no longer possess the capacity to develop into the full 
spectrum of cell types. The stem and precursor cells can be used for 
examining mechanisms of progenitor cell differentiation and identifying 
environmental signals that are specific for cell maintenance, cell 
renewal and activation of differentiation pathways. 

Research Objectives and Scope

In order to develop safe and effective stem cell-based treatments, it 
is essential to understand the signals or cues that regulate the stem 
cell capacity for self-renewal, cell fate determination, and 
maintenance of orofacial tissue homeostasis throughout life. Therefore 
the objectives of this RFA are to encourage research on: 

o  the use of human embryonic stem cell lines listed in the NIH Human 
Embryonic Stem Cell Registry. These cell lines can be used for 
examining mechanisms of progenitor cell differentiation and may also 
have characteristics that make them potentially useful for stem cell-
based therapy;
 
o  progenitor cells of the orofacial ectoderm and the cranial neural 
crest-derived mesenchyme, whose interaction during embryonic 
development gives rise to the craniofacial tissues including teeth, 
salivary glands, cartilage, bone, peripheral nerves, oral epithelium 
and smooth muscle; and

o  adult stem cells in the orofacial and other body tissues (e.g., bone 
marrow, fat, blood) that have the ability to give rise to oral, dental, 
and craniofacial tissues and organs.

Topic areas of emphasis might include but are not limited to: 

o  identification and characterization of the stem cell population(s) 
in terms of molecular markers and cell lineage in oral, dental and 
craniofacial tissues and organs;  

o  design of conditions for maintenance, ex vivo, of cell populations 
that retain their pluripotency or their multipotency;  

o  use of stem cells to understand the genetic mechanisms that regulate 
development of orofacial structures, the maintenance of tissues in 
health and the repair or regeneration of tissues following trauma and disease;

o  development of markers that distinguish stem and progenitor 
populations and gene profiles that characterize all stages of differentiation;  

o  investigation of the mechanisms that regulate self-renewal of stem 
cells in the oral epithelium, salivary gland, tooth structures and 
other craniofacial structures (e.g., bone, cartilage, muscles and nerves);

o  use of stem cell lines to identify the environmental cues and 
conditions that are required for a human embryonic stem cell to give 
rise to cells that make up the different tissues of the orofacial complex;

o  identification of signals, signaling pathways components, and 
transcriptional factors that regulate the fate(s) of transplanted human 
stem cells and their derivatives;

o  identification, characterization, and reproduction of the 
microenvironment ("niches") of stem and progenitor cells;

o  identification of the optimal type of stem cell or stem cell 
derivative for specific assays and cell therapy for orofacial diseases 
and disorders; 

o  use of animal model systems of oral, dental and craniofacial 
diseases and disorders for screening and comparing the functional 
capabilities of implanted human stem cells and their progeny.

MECHANISM OF SUPPORT
 
This RFA will use the Exploratory/Developmental R21 award mechanism.  
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. The anticipated award date is September 30, 2002.  

This RFA uses just-in-time concepts.  It also uses the modular 
budgeting format. (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).

FUNDS AVAILABLE 
 
The NIDCR intends to commit approximately $750,000 in FY 2002 to fund 4 
to 5 new grants in response to this RFA. An applicant may request a 
project period of up to 2 years and a budget for direct costs of up to 
$100,000 per year. 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. 

ELIGIBLE INSTITUTIONS
 
You may submit an application 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

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.   
 
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:

Direct your questions about scientific/research issues to:

Eleni Kousvelari, DDS, D.Sc.
Biotechnology and Biomaterials Program
Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Building 45 Room 4AN-18A
Bethesda, MD  20892
Telephone:  (301) 594-2427
FAX:  (301) 480-8318
Email:  eleni.kousvelari@nih.gov

Yasaman Shirazi, Ph.D.
Epithelial Cell Regulation and Transformation Program
Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences 
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-18C
Bethesda, MD  20892-6402
Telephone:  (301) 594-4812
FAX:  (301) 480-8318
Email:  yasaman.shirazi@nih.gov

Rochelle K. Small, Ph.D.
Developmental Biology and Mammalian Genetics Program 
Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-18D
Bethesda, MD  20892
Phone:  (301) 594-9898
Fax:  (301) 480-8318
Email:  rochelle.small@nih.gov

Guo H. Zhang, Ph.D.
Physiology, Prarmacogenetics and Injury Program
Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Building 45 Room 4AN-18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-0618 
FAX:  (301) 480-8318Phone:
Email:  guo.zhang@nih.gov

Direct your questions about peer review issues to:

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

Direct your questions about financial or grants management matters to:

H. George Hausch, Ph.D.
Acting Director,
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2904
FAX:  (301) 480-8303
Email:  George.Hausch@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 IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by March 18, 2002. The letter of 
intent should be sent to:

Eleni Kousvelari, DDS, D.Sc. Chief,
Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Building 45 Room 4AN-18A
Bethesda, MD  20892
Telephone:  (301) 594-2427
FAX:  (301) 480-8318
Email:  eleni.kousvelari@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 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.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: 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, typewritten 
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, two additional copies of the application 
must be sent to:

H. George Hausch, Ph.D.
Acting Director,
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2904
FAX:  (301) 480-8303
Email:  George.Hausch@nih.gov
 
APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
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.  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.

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. 
 
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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals:

o  Significance
o  Approach
o  Innovation
o  Investigator
o  Environment
  
	The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that, by its nature, is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of the other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will also be reviewed with respect to the following:

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

o  INCLUSION:  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 included in the section on Federal Citations, below)

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    March 18, 2002
Application Receipt Date:         April 18, 2002
Peer Review Date:                 June, 2002
Council Review:                   August, 2002
Earliest Anticipated Start Date:  September, 2002

AWARD CRITERIA

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

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 AMENDMENT 
"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://grants.nih.gov/grants/stem_cells.htm 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 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 RFA 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.

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 No. 93.121, Oral Diseases and Disorders 
Research Awards, and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.  
Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

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.


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