MICROARRAY-BASED RESEARCH ON ALCOHOL’s EFFECTS ON BEHAVIOR, NERVOUS SYSTEM
FUNCTION, AND ORGAN PATHOPHYSIOLOGY
Release Date: April 6, 2000
RFA: AA-00-004
National Institute on Alcohol Abuse and Alcoholism
(http://www.niaaa.nih.gov)
Letter of Intent Receipt Date: June 19, 2000
Application Receipt Date: July 18, 2000
THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
PURPOSE
The National Institute on Alcohol Abuse and Alcoholism (NIAAA)
announces the availability of funds for research project grants for the
study of ethanol’s effects on behavior, nervous system function, and
organ pathophysiology using emerging microarray technology. NIAAA also
encourages the formation of multidisciplinary teams of investigators--
drawing from neuroscience, genetics, molecular biology, biochemistry,
behavioral science, bioengineering, and computational biology--for this
purpose. NIAAA anticipates that such studies will aid in the
identification of genes and gene products mediating neurobiological and
behavioral changes and tissue damage induced by acute and chronic
exposure to ethanol, thereby providing new targets for the development
of medications for prevention and treatment of alcoholism and the
biomedical consequences of alcohol abuse.
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 Request for
Applications (RFA), Microarray-Based Research on Alcohol’s Effects on
Behavior, Nervous System Function, and Organ Pathophysiology, 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.
ELIGIBILITY REQUIREMENTS
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 Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) research
project grant (R01) and the NIAAA exploratory/developmental grant (R21)
award mechanisms. 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 3 years. Applications for competitive
supplements to funded NIAAA grants will also be considered responsive
to this RFA. Competitive supplement applications are limited in
duration to the funding period of the parent grant. 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
earliest anticipated award date is December, 2000 under expedited
Council review procedures.
Applicants may also submit applications for Investigator-Initiated
Interactive Research Project Grants (IRPG). Interactive Research
Project Grants require the coordinated submission of related research
project grants (R01) from investigators who wish to collaborate on
research, but do not require extensive shared physical resources. These
applications must share a common theme and describe the objectives and
scientific importance of the interchange of, for example, ideas, data,
and materials among the collaborating investigators. A minimum of two
independent investigators with related research objectives may submit
concurrent, collaborative, cross- referenced individual R01
applications. Applicants may be from one or several institutions.
Further information on these and other grant mechanisms may be obtained
from the program staff listed in the INQUIRIES section of this RFA or
from the NIAAA Web site http://www.niaaa.nih.gov/ under Research
Programs/Program Announcements.
FUNDS AVAILABLE
The NIAAA intends to commit approximately $2 million in FY 2001 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 3 years
with direct costs not to exceed $300,000 per year. Waivers for
exceptional circumstances to exceed this limit should contact Program
Staff as indicated under Inquiries below. Under the R21 mechanism,
direct costs are limited to $100,000 per year. (See Program
Announcement PA-99-131, NIAAA Exploratory/Developmental Grant
Program, http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html,
for a complete description of the R21 mechanism.) Because the nature
and scope of the research proposed might vary, it is anticipated that
the size of awards 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.
RESEARCH OBJECTIVES
Background
Microarrays represent a powerful new technology that has been applied
to a variety of research questions. For example, oligonucleotide/cDNA
arrays have been used to analyze the overall expression patterns of
cells and tissues under various conditions, to identify amplified
regions of the genome, and to search for specific changes in gene
expression caused by variants or mutant alleles.
It has been shown that administration and/or withdrawal of ethanol
induces the expression of specific genes and their protein products.
The precise changes in gene expression depend on the dose and duration
of ethanol exposure, and the tissue preparation under study. It seems
likely that some of these changes in gene expression play a crucial
role in mediating physiological and behavioral responses to ethanol.
Therefore, it is of interest to use microarrays to determine how
ethanol affects the overall gene expression pattern, and ultimately the
overall protein expression pattern, in specific target cells.
Research has shown that particular regions of the brain, such as the
nucleus accumbens, ventral tegmental area, amygdala and prefrontal
cortex are important sites in the response to ethanol. The critical
changes in gene expression in these and other target brain regions may
be relatively small quantitatively. Furthermore, different brain
regions may respond in alternate or even opposite ways to ethanol, and
within any region, only a particular subset of neurons may play a
critical role in responses to ethanol. It is therefore of paramount
importance to define the regions of the brain to be analyzed as
precisely as possible, so that the signal-to-noise ratio is high.
Ultimately, analysis of post-mortem human or mammalian tissue with
microarrays may provide a comprehensive profile of gene and/or protein
expression in particular cell types, which collectively characterizes
the physiological states of neurons associated with behavioral
phenomena such as tolerance, dependence, and withdrawal. This approach
can also highlight differences in gene expression between individuals
(or strains of animal) with high vs. low responses to ethanol (e.g.,
sedation, ataxia, withdrawal, locomotor activation).
Ethanol is a potent teratogen that causes a spectrum of brain damage,
including fetal alcohol syndrome. Depending on dose of ethanol and
timing of exposure, specific brain regions and cell populations are
differentially affected. Analysis of tissues with microarrays could
provide insights about the relationship between functional alterations
during development and subsequent neurological and behavioral deficits.
Responses in plasticity to specific prenatal and postnatal
manipulations can also be evaluated.
The initiation and progression of ethanol-induced organ pathogenesis is
a complex process that involves the induction of genes and their
protein products at multiple sites. Elucidating the specific molecular
targets of ethanol’s actions in specific organs will facilitate the
development of appropriate drug interventions. As with brain, it will
be important to delineate specific cell populations for evaluation with
microarrays.
The technology and analytic methodology for micorarray-based studies
are now at a relatively early stage of development. NIAAA encourages
studies using current technology, as well as those which incorporate
development and improvement of microarray-based methods.
Areas of Interest
Current areas of research that are considered relevant include but are
not limited to:
o Characterization of overall gene expression pattern of neural
tissues or cells in response to acute or chronic exposure to ethanol.
o Identification of unique patterns of gene expression due to prenatal
and/or neonatal exposure to ethanol.
o Identification of unique patterns of gene expression describing
organ system pathology due to ethanol exposure, e.g., cardiomyopathy,
pancreatitis, alcoholic liver disease.
o Identification of unique patterns of gene expression associated with
specific behavioral responses to ethanol.
o Comparison of gene expression patterns in strains of animals
differing in specific responses to ethanol (e.g., consumption,
sedation, and withdrawal).
SPECIAL REQUIREMENTS
SHARING OF MATERIALS GENERATED UNDER THIS RFA
Projects funded under this RFA are likely to lead to the creation of
new gene arrays, gene expression data, analytic methods for gene
expression patterns, and other research tools which will be of great
value to the broader research community, beyond the laboratories which
will create them. NIAAA strongly encourages the maximal dissemination
of these tools to the broader research community to ensure that they
may be exploited to their full potential. NIAAA accordingly requires
applicants who respond to this RFA to propose detailed plans for
sharing the research resources that will be generated through the
grant.
It is expected that the investigator’s resource sharing plan will
include a description of the mechanisms proposed for wide distribution
of resources with investigators in the scientific community, and a
timetable for distribution of resources. The reviewers will make an
administrative comment on the adequacy of the proposed plan for
resource sharing. (This comment will not affect the priority score of
the proposal.) NIAAA program staff will consider the adequacy of the
plan in determining whether to recommend an application for award. The
sharing plan as approved, after negotiation with the applicant as
necessary, shall become a condition of the grant award. Where
appropriate, grantees may work with the private sector to make
resources available to the wider research community at a reasonable
cost. Applicants may request funds to defray the costs of sharing
resources, with adequate justification. For more detailed guidance on
NIH’s policies on resource sharing, applicants are referred to
Principles and Guidelines for Recipients of NIH Research Grants and
Contracts on Obtaining and Disseminating Biomedical Research
Resources, http://www.ott.nih.gov/policy/rt_guide_final.html.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH
INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and
justification is provided 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 "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which was published in the Federal
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the
Web at http://grants.nih.gov/grants/guide/notice-files/not94-100.html.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH
INVOLVING HUMAN SUBJECTS
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 address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html .
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.
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 a 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.
LETTER OF INTENT
Prospective applicants are asked to submit 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 Institute staff to
estimate the potential review workload and avoid conflict of interest
in the review.
The letter of intent is to be sent to
RFA-AA-00-004,
Extramural Project Review Branch,
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409, MSC 7003
Bethesda, MD 20892-7003
by the letter of intent receipt date listed in the heading of this RFA.
APPLICATION PROCEDURES
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: GrantsInfo@nih.gov. Applications are
also available at: http://grants.nih.gov/grants/forms.htm.
SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS
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.
BUDGET INSTRUCTIONS
All applications will use the Modular Grant format and request direct
costs in $25,000 modules. 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 FACE PAGE - Items 7a and 7b should be completed, indicating
Direct Costs (in $25,000 increments 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.
DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form
Page 4 of the PHS 398. It is not required and will not be accepted with
the application.
BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not
required and will not be accepted with the application.
NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget
Narrative page. (See
http://grants.nih.gov/grants/funding/modular/modular.htm, for sample
pages.) At the top of the page, enter the total Direct Costs requested
for each year. This is not a Form page. Under Personnel, list key
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 F&A) 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 key 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.
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:
http://grants.nih.gov/grants/funding/modular/modular.htm. - 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, and- List selected peer-reviewed publications, with
full citations.
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. 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.
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.
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 sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf 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:
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:
RFA :AA-00-004
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409, MSC 7003
Bethesda, MD 20892-7003
Rockville, MD 20852 (for express/courier service)
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.
REVIEW CONSIDERATIONS
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. 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 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 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 NIAAA 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 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? (For the R21 mechanism, a strong rationale and conceptual
framework are normally sufficient for establishing the feasibility of
the project, in lieu of extensive preliminary data.)
(3) Innovation: Does the project employ novel concepts, approaches, or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies? Does the applicant propose novel
approaches to improve the accuracy, efficiency, and usefulness of
microarray-based assays?
(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 support?
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 evaluated.
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 review group will also comment on plans for data sharing.
Schedule
Letter of Intent Receipt Date: June 19, 2000
Application Receipt Date: July 18, 2000
Peer Review Date: October 2000
Earliest Anticipated Start Date: December, 2000 under expedited
Council review procedures.
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
o adequacy of plans for data sharing
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to
clarify any issues or questions from potential applicants is
welcome.
Direct inquiries regarding programmatic issues on neuroscience and
behavior to:
Robert W. Karp, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-2239
FAX: (301) 594-0673
Email: rkarp@willco.niaaa.nih.gov
Direct inquiries regarding programmatic issues on prenatal ethanol
exposure and ethanol-induced organ pathology to:
Laurie Foudin, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-0912
FAX: (301) 594-0673
Email: lfoudin@willco.niaaa.nih.gov
Direct inquiries regarding fiscal matters to:
Judy Simons
Grants Management Branch
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-2434
FAX: (301) 443-3891
Email: jsimons@willco.niaaa.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance
No. 93.273. Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under NIH grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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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