Release Date:  November 13, 2000

RFA: HL-01-007

National Heart, Lung, and Blood Institute 
National Institute of Diabetes and Digestive and Kidney Diseases 
National Institute of Neurological Disorders and Stroke  

Letter of Intent Receipt Date: February 6, 2001
Application Receipt Date: March 12, 2001



The Cellular Hematology Scientific Research Group, Division of Blood Diseases 
and Resources, NHLBI, the Hematology Program, Division of Kidney, Urologic, 
and Hematologic Diseases, NIDDK, and the Repair and Plasticity Program, NINDS 
announce the availability of a Request for Applications (RFA) on the above 
subject.  The objective of this initiative is to promote the thorough 
exploration and characterization of stem cell plasticity in hematopoietic and 
non-hematopoietic tissue.  Research efforts are needed to test stem cell 
plasticity in a rigorous manner.  It is of particular importance to 
characterize cellular and molecular mechanisms that lead to the capacity of 
adult stem cells with hematopoietic potential to express other potentials and 
precursor cells of adult non-hematopoietic tissues to express hematopoietic 
potential.  Other areas of high interest include the ability of stem cells 
from non-neuronal tissues to differentiate along neuronal and glial lineages.


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 

Domestic applications may include foreign components.  FOREIGN INSTITUTIONS: 
Awards under this announcement may be made to foreign institutions provided 
the application (1) is of high scientific merit and (2) offers a special 
opportunity for furthering research programs through the use of unusual 
talents, resources, populations, or conditions in other countries which are 
not readily available in the United States or which augment existing U.S. 
resources.  All current policies and requirements that govern the research 
grant programs of the NIH will apply to grants awarded under this RFA.


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 Request for Applications (RFA), 
"Stem Cell Plasticity in Hematopoietic and Non-Hematopoietic Tissue" is 
related to one or more of the priority areas.  Potential applicants may obtain 
a copy of "Healthy People 2010" at


This RFA will use the National Institutes of Health (NIH) individual research 
project grant (R01) mechanism of support.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  The total project period for an application submitted in response 
to this RFA may not exceed four (4) years.  This RFA is a one-time 
solicitation.  Future unsolicited competing continuation applications will 
compete with all investigator-initiated applications and be reviewed according 
to the customary peer review procedures.  The anticipated award date is 
September 30, 2001.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at

For this RFA, funds must be requested in $25,000 direct cost modules and a 
maximum of ten modules ($250,000 direct costs) per year may be requested.  
Only limited budget information will be required and any budget adjustments 
made by the Initial Review Group will be in modules of $25,000. The 
APPLICATION PROCEDURES section of this RFA provides specific details of  
modifications to standard PHS 398 application kit instructions.

Applicants, who will plan and execute their own research programs, are 
requested to furnish their own estimates of the time required to achieve the 
objectives of the proposed research project.  Up to four years of support may 
be requested.  At the end of the official award period, renewal applications 
may be submitted for peer review and competition for support through the 
regular grant program of the sponsoring Institutes.  It is anticipated that 
support for the present program will begin September 30, 2001.  Administrative 
adjustments in project period or amount of support may be required at the time 
of the award. All current policies and requirements that govern the research 
grant programs of the NIH will apply to grants awarded in connection with this 


The three sponsoring Institutes intend to commit approximately $2,000,000 each 
for total costs for the first year of support (totaling $6,000,000)in FY 2001 
to fund twelve to eighteen new grants submitted 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 (ten modules of $25,000).  Facilities and 
administrative costs will be awarded based on the negotiated rates.  Because 
the nature and scope of the research proposed may vary, it is anticipated that 
the size of each award will also vary. Although the financial plans of the 
sponsoring Institutes is to 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.

Although not formally participating in this request for applications, the 
National Institute on Aging is interested in research on the plasticity of 
stem cells from hematopoietic and non-hematopoietic tissue in generating 
neuronal, astroglial and microglial cells of the nervous system.  Also, the  
National Cancer Institute has an evolving interest in the application of 
pluripotent stem cell technologies to cancer therapy and the understanding of 
the etiology of malignant disease. 



Stem cell research offers enormous potential for treating devastating 
malignant and non-malignant diseases.  Recently, a number of groups have 
reported that stem cells derived from adults may be capable of surprising 
plasticity or versatility.  Investigators reported that after bone marrow 
transplantation, donor-derived cells could be found in non-hematopoietic 
tissues.  These tissues included astroglia in the central nervous system, 
skeletal muscle, liver oval cells, cardiomyocytes, vascular-endothelial cells, 
and bone forming osteoblasts.  In addition, bone marrow stromal cells from 
rats and humans can apparently give rise to large numbers of cells with 
neuronal properties under specific culture conditions.  Also, muscle derived 
material was reported to display hematopoietic activity.  In these studies, 
diagnostic cell surface markers have shown the reconstitution of both myeloid 
and lymphoid cell lineages after transplantation.  Neuronal cells have also 
been reported to give rise to progenitors of all blood lineages and to 
demonstrate myogenic potential.  Thus, increasing evidence suggests that adult 
cells could have far greater differentiative plasticity even at advanced 
stages of their differentiation programs than previously thought.  The 
plasticity concept resembles the documented phenomenon known as 
transdifferentiation.  However, the extent to which the transdifferentiation 
principle can be generalized to current findings is unknown.

Findings such as those described above raise many unanswered and intriguing 
questions regarding the biology of stem cells and the routes they take to 
express their differentiation potential.  This RFA is developed to encourage 
research to substantiate stem cell plasticity and to characterize cellular, 
molecular, and genetic mechanisms that allow cells to express plasticity.   

The National Heart, Lung, and Blood Institute sponsored a meeting entitled, 
"Working Group on Stem Cell Plasticity" in March, 2000 to assess the state-of-
science in this area. The final report is located at  

For the purpose of this announcement, plasticity is defined to mean either (1) 
non-hematopoietic lineage potential in hematopoietic stem cells or
(2) hematopoietic potential in stem cells of other systems.  It is 
acknowledged that cells from different tissue sources may have different 
potentials.  Rigorous studies which establish and address the breadth of 
plasticity and its physiological relevance, and the molecular and cellular 
requirements to reveal plasticity including the identification of necessary 
stem/progenitor cell markers, timing, and microenvironmental cues, are 
important research areas to pursue.  This initiative is particularly directed 
to the use of well-defined, in vivo systems to assess stem cell plasticity, 
such as those established for the study of hematopoietic stem cells or for 
region-specific differentiation and integration into the nervous system.   In 
addition, projects exploring potential hematopoietic or neuronal repertoires 
of mesenchymal precursor cells would be directly relevant to this RFA.  
However, studies which focus on stem cell expansion or differentiation within 
a given tissue (e.g., hematopoietic stem cell expansion with cytokines, 
signals required for differentiation of neurons from neuronal stem cells) are 
not responsive.  In addition, basic and developmental mesenchymal cell biology 
projects are not responsive to this RFA.

Examples of research needs are identified below.

o  Rigorous testing for stem cell plasticity through application of clonal 
approaches (e.g., micro-manipulation of single cells, limiting dilution 
analyses, retroviral insertion marking, etc.)

o  Determine whether individual cells with hematopoietic potential can express 
other potentials.

o  Determine whether individual cells with other potentials (muscle, CNS, 
etc.) in other sites of the body also have hematopoietic potentials.

o  Conduct comparative studies between adult somatic cells with pluripotential 
properties with the aim of defining a rigorous phenotype for somatic stem 
cells from specific tissues.  Also, comparative studies between somatic stem 
cells and embryonic stem cells to identify the extent that individual primary 
and ES cells share properties are of interest.  

o  Examine the mechanisms of trafficking, homing, engraftment, and integration 
of stem cells in the host with the emphasis on the capability of cells derived 
from one tissue to engraft into another.  

o  Develop novel approaches to manipulate transplantable cells and/or the host 
in order to facilitate production of desired cell types for stem cell 

o  Develop clinically relevant small and large animal models to make use of 
the concept of stem cell plasticity.

The above examples of research approaches are not meant to be all inclusive or 
restrictive. Prospective applicants are encouraged to develop their own ideas 
of research on which to address the goals of the RFA. 


Upon initiation of the program, sponsoring Institutes will arrange annual 
meetings to encourage the exchange of information among investigators who 
participate in this program.  In the preparation of the budget for the grant 
application, applicants should include travel funds for 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 

This initiative is particularly directed to the use of well-defined, in vivo 
systems to assess stem cell plasticity (for the purpose of this announcement 
see definition above) such as those established for the study of hematopoietic 
stem cells or for region-specific differentiation and integration into the 
nervous system.  In addition, projects exploring potential hematopoietic or 
neuronal repertoires of mesenchymal precursor cells would be directly relevant 
to this RFA.  However, studies which focus on stem cell expansion or 
differentiation within a given tissue (e.g., hematopoietic stem cell expansion 
with cytokines, signals required for differentiation of neurons from neuronal 
stem cells) are not responsive.  In addition, basic and developmental 
mesenchymal cell biology projects are not responsive to this RFA.


All investigators proposing research using human pluripotent stem cells should 
read the National Institutes of Health Guidelines for Research Using Human 
Pluripotent Stem Cells (the Guidelines) published in the Federal Register on 
August 25, 2000 and is available at the following URL address:

Details on the approval process and the procedures for submitting the required 
documentation of compliance are at the following URL address:


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 biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000  
A complete copy of the updated Guidelines are available at The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


Prospective applications are asked to submit, by February 6, 2001, a letter of 
intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted. 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 
staff to estimate the potential review workload and to plan the review.  The 
letter of intent is to be mailed, or faxed, to Dr. Deborah Beebe at the 
address listed under INQUIRIES.


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year. The total direct costs must 
be requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative (F&A) costs] for the initial budget 
period.  Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

of the PHS 398. It is not required and will not be accepted with the 

categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See for sample 
pages.) At the top of the page, enter the total direct costs requested for 
each year.  This is not a Form page.

o Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000. List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of all personnel, and the role 
on the project. Indicate whether the collaborating institution is foreign or 
domestic. The total cost for a consortium/contractual arrangement is included 
in the overall requested modular direct cost amount.  Include the Letter of 
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual"s qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for all 
key personnel, following the instructions below. No more than three pages may 
be used for each person. A sample biographical sketch may be viewed at:

- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on       
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations,

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied  in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further review.

Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research.  If so,
a letter of agreement from either the GCRC program director or principal
investigator could be included with the application.

The RFA label available in the PHS 398 (rev. 4/98) 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 

The sample RFA label available at:  has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

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 Dr. Deborah Beebe at the address listed under INQUIRIES.

Applications must be received by the application receipt date listed in the 
heading of this RFA (MARCH 12, 2001).  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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the sponsoring Institutes staff.  Incomplete and/or non-
responsive applications will be returned to the applicant without further 
consideration.  Studies which focus on stem cell expansion or differentiation 
within a given tissue (e.g., hematopoietic stem cell expansion with cytokines, 
signals required for differentiation of neurons from neuronal stem cells) are 
not responsive to this RFA.  In addition, basic and developmental mesenchymal 
cell biology projects are not responsive.

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 receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the appropriate National Advisory Council or Board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments 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.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) 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?

(2) 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?

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

(4) 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)?

(5) 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 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  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.


The anticipated date of award is September 30, 2001.  Funding decisions will 
be made on the basis of scientific and technical merit as determined by peer 
review, program needs and balance, and the availability of funds.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:

Dr. Helena O. Mishoe
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10156
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868

Dr. David G. Badman
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 621 MSC 5458
6707 Democracy Blvd.
Bethesda, MD 20892-5458
Telephone: (301) 594-7717
FAX: (301) 480-3510

Dr. Arlene Y. Chiu
Repair and Plasticity Program
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 2206, MSC 9525
Bethesda, MD. 20892-9525
Telephone:	(301) 496-1447
FAX:	(301) 480-1080

Direct inquiries regarding review issues, send letter of intent and two copies 
of the application to:

Dr. Deborah Beebe
Chief, Review Branch
Division of Extramural Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD 20892-7924 (20817 for express mail)
Telephone: (301) 435-0270
FAX: (301) 480-3541

Direct inquiries regarding fiscal matters to:

Ms. Suzanne White
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic Assistance No. 
93.839, 93.848, and 93.854.  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 and Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

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