STEM CELL RESEARCH FOR ALCOHOL-RELATED DISORDERS
Release Date: March 13, 2002
RFA: RFA-AA-02-010
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
(http://www.niaaa.nih.gov)
LETTER OF INTENT RECEIPT DATE: April 15, 2002
APPLICATION RECEIPT DATE: May 15, 2002
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 purpose of this RFA is to foster research on 1) the impact of alcohol
exposure on embryonic and adult stem cell biology, 2) the capacity of stem
cells to replace tissues and/or restore function directly at sites of alcohol-
induced organ and fetal damage in animal models, 3) the use of stem cells as a
tool to further elucidate mechanisms of alcohol dependence and alcohol-related
pathological conditions, such as brain degeneration, alcoholic liver disease,
pancreatitis, and fetal alcohol syndrome, and 4) restoration of normal
function in alcohol-damaged tissues using stem cells in combination with gene
therapy.
RESEARCH OBJECTIVES
Background
Long-term alcohol abuse is known to cause pathologies in a number of the
body"s organ systems. Those disorders most commonly associated with chronic
alcohol consumption include alcoholic liver disease (ALD), pancreatitis,
cardiovascular disease, endocrine dysfunction, osteoporosis, cancer, and
immune dysfunction. Heavy alcohol intake is also associated with structural
and functional changes in the adult and developing central nervous system,
manifested by brain atrophy and neurodegeneration, as well as
neurodevelopmental disorders such as fetal alcohol syndrome. Brain regions
most severely affected by chronic alcohol consumption, as well as by prenatal
alcohol exposure, are the frontal cortex, cerebellum, hippocampus, and the
hypothalamus.
Embryonic and adult stem cells offer powerful tools to elucidate mechanisms
underlying normal biological functions and the mechanisms by which alcohol
disrupts normal functions in susceptible organs. They may also prove valuable
in developing therapeutic approaches for treating alcohol-induced
physiological impairments and overt organ damage. Although rapid progress has
been made in characterizing embryonic and adult stem cells and their capacity
to proliferate, migrate, differentiate, and integrate into multiple tissues,
very little is known about how alcohol affects these processes. For example,
does alcohol exposure alter normal stem cell fate determination and
plasticity? Does chronic alcohol consumption alter the number and
availability of autologous stem cells and their biological properties? Does
alcohol exposure alter the biochemical environment of tissues, thus
interfering with the capacity of stem cells to establish contact,
differentiate and function in target tissues? Does alcohol interfere with the
capacity of endogenous stem cells to limit or repair alcohol-induced pathology
in various tissues? These are some of the fundamental research questions that
need to be addressed.
It now appears that cell fate changes are a natural property of stem cells and
may be involved in tissue homeostasis and repair of tissue damage. For
example, adult neural stem cells have the capacity to express a variety of
neuronal cell types, and hematopoietic stem cells have been shown to form
functional liver hepatocytes. Evidence suggests that circulating stem cells
home to niches within an organ, where signaling factors stimulate
differentiation into the desired cell types. The effects of different
patterns of chronic alcohol exposure on the niche environments essential for
engrafting and differentiation of stem cells needs further investigation.
Although more research is needed to improve stem cell isolation techniques,
use of autologous adult stem cells for tissue-replacement therapy could
represent a major advantage by avoiding immune rejection. However, it is
unclear whether chronic alcohol consumption would also destroy the host"s
natural supply of stem cells and/or alter their capacity to respond to
cellular signals in target tissues. In liver regeneration, both oval stem
cells and hematopoietic stem cells are key players, thus, the capacity of
these cells to regenerate the architecture necessary to support liver function
after chronic alcohol exposure also needs to be studied.
Stem cells have particularly exciting potential in combination with genetic
engineering strategies and gene therapy. Stem cells stably expressing
transgenes may be used to deliver soluble molecules to specific sites by
migrating and differentiating into the target tissue. In addition to tissue
repair, stem cells have the potential to control progression of disease. For
example, engrafted stem cells engineered to overexpress proteins in specific
brain regions potentially could modulate host levels of critical
neurotransmitters involved in pathological alcohol consumption. Furthermore,
transgene expression in a patient"s own somatic stem cells should prevent the
adverse immune responses often seen with adenovirus and other gene therapy
vectors. Combination therapy is likely to be most useful for certain alcohol-
related disorders where delivery of genes will compensate for impaired
enzymes, peptides, and neurotransmitters.
Research Objectives and Scope
This RFA solicits research on the application of stem cells to alcohol-
relevant problems. The use of stem cells derived from any approved source,
including human embryonic stem cell lines listed in the NIH Human Embryonic
Stem Cell Registry (see REQUIRED FEDERAL CITATIONS below for additional
information) is encouraged. Although some types of clinical research would be
appropriate for this RFA, clinical trials are outside the scope of the RFA.
Examples of research that would be responsive to this RFA are identified
below. These research areas are not intended to be inclusive or restrictive.
o Studies on the effects of alcohol on in vivo and ex vivo stem cell
viability and differentiation into specific cell types including neurons,glial
cells, liver cells, pancreatic cells, cardiomyocytes, etc.
o Biochemical and physiological studies examining the capacity of stem cells
to integrate with host tissues and to restore impaired tissue function under
conditions of chronic alcohol exposure.
o Studies to determine the effects of alcohol dose and exposure pattern on
the long-term fate of transplanted stem cell-derived populations in animal
models of alcohol-induced tissue injury including brain and liver damage.
o Studies to assess the functional integrity of autologous stem cells in
animal models of prenatal, adolescent, and adult alcohol exposure.
o Studies to determine the effectiveness of stem cells engineered to
overexpress candidate genes/proteins to offset/reverse neural maladaptive
responses to alcohol, such as tolerance, dependence, craving, and withdrawal.
o Development, in animal models, of stem cell transplantation and combination
stem cell/gene therapy approaches to protect against or prevent alcohol-
induced tissue damage, or hasten repair of integral processes that are
sensitive to alcohol.
MECHANISM OF SUPPORT
This RFA will use NIH research project grant (R01), NIAAA
exploratory/developmental grant (R21), and NIAAA small grant (R03) award
mechanisms. As an applicant you will be solely responsible for planning,
directing, and executing the proposed project. Exploratory/developmental
grants (R21) are limited to three years for up to $100,000 per year for direct
costs. (See PA-99-131, "NIAAA Exploratory/Developmental Grant Program,"
https://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete
description of the R21 mechanism.) Small grants (R03) are limited to two years
for up to $50,000 per year for direct costs. (See PAR-99-098, "NIAAA Small
Grant Program," https://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html,
for a complete description of the R03 mechanism.) This RFA is a one-time
solicitation. Future unsolicited, competing 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
https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $300,000
or less, use the modular format. Otherwise follow the instructions for non-
modular research grant applications.
FUNDS AVAILABLE
The NIAAA intends to commit approximately $2 million in FY 2002 to fund six to
eight new and/or competitive continuation grants in response to this RFA. An
applicant may request a project period of up to five years and a budget for
direct costs of up to $300,000 per year, using the R01 support mechanism. An
applicant may request a shorter project period and lesser amount of support,
using the R03 or R21 mechanism, as described above. 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 NIAAA 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 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 (only domestic organizations are eligible for the R03
mechanism)
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
Investigators wishing to obtain support for research relevant to this RFA who
lack expertise in alcohol research are encouraged to collaborate with
investigators who are experienced in alcohol research, insofar as such
experience will prove essential for proper study design and data analysis.
Investigators desiring to establish such collaborations are encouraged to
contact the individuals listed under WHERE TO SEND INQUIRIES below.
Investigators who lack expertise in stem cell research should seek
collaboration with researchers who are familiar with aspects of stem cell
research that are relevant to the proposed research.
Awardees will be expected to attend one joint meeting every two years in or
near Washington, DC, in order to review progress and exchange information.
Sufficient funds to support attendance at these meetings should be included in
the budget.
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:
Lisa Neuhold, Ph.D.
Neuroscience and Genetics Programs
Neurosciences and Behavioral Research Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 594-6228
FAX: (301) 594-0673
Email: lneuhold@willco.niaaa.nih.gov
Laurie Foudin, Ph.D.
Tissue Injury and Fetal Alcohol Research Programs
Biomedical Research Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-9812
FAX: (301) 594-0673
Email: Lfoudin@nih.gov
o Direct your questions about peer review issues to:
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-4375
o Direct your questions about financial or grants management matters to:
Ms. Judy Simons
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-4704
FAX (301) 443-3891
Email: jsimons@willco.niaaa.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 NIAAA 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:
RFA-AA-02-010
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD 20892-7003
Rockville, MD 20852 (for express/courier service)
FAX: (301) 443-6077
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
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SUPPLEMENTAL INSTRUCTIONS: Applicants who plan to submit a small grant (R03)
application must follow the instructions provided in PAR-99-098, "NIAAA Small
Grant Program," https://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting
up to $300,000 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
https://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
https://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:
https://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:
AA-02-010
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD 20892-7003
Rockville, MD 20852 (for express/courier service)
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 NIAAA. Incomplete applications will be returned to the
applicant without further consideration. And, if the application is not
responsive to the RFA, CSR staff may contact the applicant to determine
whether to return the application to the applicant or submit it for review in
competition with unsolicited applications at the next appropriate NIH review
cycle.
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 NIAAA 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 NIAAA National Advisory Council on
Alcohol Abuse and Alcoholism.
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. (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.
o OTHER REVIEW CRITERIA: Additional considerations pertinent to the review of
Exploratory/Developmental Grant (R21) and Small Grant (R03) applications
include: 1) Pilot/feasibility studies contain little or no preliminary data.
Review should focus on whether the rationale for the study is well developed
and whether the proposed research is likely to generate data that will lead to
a regular research project grant or full-scale clinical trial. Adequate
justification for the work may be provided through literature citations, data
from other sources, or investigator-generated data. 2) Because the research
plan of R03 applications is limited to ten pages, these applications may not
have the level of detail or extensive discussion normally found in an R01
application. Review emphasis should be placed on conceptual framework and
general approach to the problem, with less emphasis on methodological details.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: April 15, 2002
Application Receipt Date: May 15, 2002
Peer Review Date: July-August 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 28, 2002
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
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 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are
available at
https://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
https://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
https://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 https://grants.nih.gov/grants/stem_cells.htm and at
https://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
https://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. 93.273, 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 https://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.