BASIC RESEARCH ON MESENCHYMAL STEM CELL BIOLOGY
 
RELEASE DATE:  March 6, 2002
 
RFA:  HL-02-018
 
National Heart, Lung and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov)
 
LETTER OF INTENT RECEIPT DATE: May 15, 2002 
APPLICATION RECEIPT DATE: June 20, 2002
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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  

Preclinical studies suggest mesenchymal stem cells facilitate hematopoietic 
stem cell transplantation while decreasing immune rejection of allogeneic 
transplants.  In addition, mesenchymal stem cells have been demonstrated to 
differentiate into a variety of non-hematopoietic tissues including bone, 
cartilage, tendon, fat, skeletal and cardiac muscle, and early progenitors of 
neural cells.  The National Heart, Lung and Blood Institute and National 
Institute on Aging invite applications on basic research on mesenchymal stem 
cell biology that will provide the basis for clinical application to 
hematopoietic and non-hematopoietic stem cell transplantation.
 
RESEARCH OBJECTIVES

Background

Mesenchymal stem cells are pluripotent progenitor cells located in bone 
marrow that can differentiate into a variety of non-hematopoietic tissues 
including bone, cartilage, tendon, fat, muscle, and early progenitors of 
neural cells.  However, mesenchymal stem cells have not been shown to produce 
blood cells.  Preclinical and early clinical safety studies are paving the 
way for further applications of these cells in the field of transplantation 
with respect to hematopoietic support, immunoregulation, graft facilitation, 
and potentially gene therapy.   Preclinical studies suggest mesenchymal stem 
cells may enhance the ability of the bone marrow microenviornment to support 
hematopoiesis after stem cell transplantation.  Moreover, an important role 
in immunoregulation is suggested by reports that these cells can suppress T 
cell activation without inducing allogeneic anergy.  These findings may have 
important applications for stem cell transplantation, organ transplantation, 
and other regenerative and reparative therapies.

Scope

The therapeutic implication of these studies for hematopoietic and non-
hematopoietic stem cell transplantation is tremendous.  However, the ability 
to identify the most appropriate population and assay methods that 
characterize the clinical potential of candidate human mesenchymal stem cells 
are currently lacking.  Isolation and characterization standards would permit 
the comparison of results and this would significantly enhance multi-
disciplinary, collaborative approaches to these important problems.  Studies 
in this area will help ensure that future clinical protocols will be based on 
a solid foundation of basic science.  The scope of this RFA also includes 
applications that address the undefined lineage relationship of hematopoietic 
and mesenchymal stem cells.  In addition, comparative studies of mesenchymal 
stem cells and postnatal stem cells are also encouraged.  However, the scope 
of the RFA is not limited to the areas defined above and research 
applications addressing other important areas of mesenchymal cell biology are 
encouraged.

Examples of research areas of interest:
 
o Basic mesenchymal stem cell biology.

o Studies defining the lineage relationship between mesenchymal stem cells 
and other stem cells.

o Novel markers for mesenchymal stem cell identification to enhance isolation 
and purification and to facilitate ex vivo stem cell expansion systems.

o Refinement of cellular culture systems and elucidation of the molecular
events that permit ex vivo expansion of mesenchymal stem cells.

o Identification and characterization of functional, molecular regulators of
mesenchymal stem cell self-renewal and commitment.

o In vivo and in vitro assay systems for human mesenchymal stem cells.

o Role of growth factors, cytokines, receptors, transmembrane signaling,
marrow microenvironment, and adhesive proteins in mesenchymal stem cell 
interactions and hematopoiesis.

o Identification and characterization of mechanisms by which mesenchymal stem 
cells increase stem cell engraftment.

o Histocompatibility and allo-interactions, mechanism of induction of
transplant tolerance, minimizing the graft vs. host effect and graft 
rejection for organ and cellular transplants of heart, lung, or blood 
tissues.

o Studies on the biology of mesenchymal stem cells in aging including changes 
in potential, population dynamics, mobilization, and interaction with the 
aging environment.

o Basic research studies to develop future mesenchymal stem cell therapies to 
correct genetic diseases or for repair or regeneration of tissue or organ 
damage.

o Basic research studies to develop future gene therapy approaches using 
mesenchymal stem cells as targets for gene insertion and long-term expression 
of normal genes using viral and non-viral approaches to gene transduction.
 
MECHANISM OF SUPPORT
 
This RFA will use NIH R01 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 April 1, 
2003.

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 two participating Institutes intends to commit approximately $ 2,400,000 
to fund 5 to 6 new competitive grants in response to this RFA. An applicant 
may request a project period of up to four years and a budget for direct 
costs of up to $ 250,000 per year. 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 sponsoring Institutes 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 (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

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

ANNUAL INVESTIGATOR MEETINGS:  Upon initiation of the program, the NHLBI and 
NIA will sponsor joint annual meetings to encourage the exchange of 
information among investigators who participate in this program, perhaps in 
conjunction with other Institute sponsored stem cell programs.  In the 
preparation of the budget for the grant application, applicants should 
Include travel funds for the one meeting each year to be held in Bethesda, 
Maryland.  Applicants should also include a statement in the applications 
indicating their willingness to participate in such meetings.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA 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:

Dr. John W. Thomas
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Room 10154
6701 Rockledge Drive
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 451-5453
Email:  ThomasJ@nhlbi.nih.gov 

Dr. Jill L. Carrington
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue Suite 2C231
Bethesda, MD   20892
Telephone:  (301) 496-6402
FAX: (301) 402-0010
Email:  CarringtonJ@nia.nih.gov 

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

Suzanne White
National Heart, Lung, and Blood Institute
6701 Rockledge Drive / Room 7154 / Mail Stop 7926
Bethesda, MD  20817-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  WhiteSA@nhlbi.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 the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Anne P. Clark, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-0730
Email:  ClarkA@nhlbi.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 as well 
as all five collated sets of Appendix material must be sent to:
 
Anne P. Clark, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-0730
Email:  ClarkA@nhlbi.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.

Principal investigators should not sent supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has 
been received.  If you have not received such a letter within three weeks 
after submitting the application, contact Dr. Anne Clark at the address 
listed under Submitting an Application.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI and NIA. 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 NHLBI in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will:

o Receive a written critique
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 second level review by the Heart, Lung and Blood National 
Advisory Council or the National Advisory Council on Aging.
 
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 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.

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: May 15, 2002
Application Receipt Date:  June 20, 2002
Peer Review Date: October/November 2002
Council Review: February 6-7, 2003
Earliest Anticipated Start Date: April 1, 2003

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 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and 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 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 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.

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. 93.839 and 93.866, 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.
http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html. 


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.