Release Date:  December 17, 2001

RFA:  RFA-AA-02-007

National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  March 15, 2002
Application Receipt Date:       April 15, 2002



NIAAA has previously provided funding to two Mouse Mutagenesis Centers to 
create chemically induced single-gene mutants of mice with altered behavioral 
responses to ethanol.  These mutant mice, which will begin to become 
available to the research community in 2002, will be valuable new tools for 
elucidating the physiological mechanisms of ethanol's effects on behavior and 
nervous system function.  NIAAA is issuing this RFA in order to promote the 
extraction of greatest possible amount of information from these mutants, by 
means of the following types of studies:
- Identification of the mutated genes responsible for the altered ethanol-
related behavior exhibited by the mutant mice.
- Behavioral, anatomical, physiological, and pharmacological studies on these 
mutants to determine the mechanisms by which the mutations they bear cause 
alterations in their ethanol-related behavior.
- High-throughput mutant screens to identify additional mutant mice with 
altered ethanol-related behavioral or neurological phenotypes.


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), Title of RFA, is related to one or more of the priority 
areas.  Potential applicants may obtain a copy of "Healthy People 2010" at


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 


This RFA will use the National Institutes of Health (NIH) R01 and 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 
three years (R21), or five years (R01).  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 
28, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at


NIAAA intends to commit approximately $1.5 million (total costs) in FY 2003 
to fund 6-8 new and/or competitive continuation grants in response to this 
RFA. An applicant may request a project period of up to three years and a 
budget for direct costs of up to $100,000 per year for R21 grants, or up to 
five years with no budget restrictions for R01 grants. However, applicants 
must request permission in advance from NIAAA to submit an application for 
which the budget exceeds $500,000 direct costs in any year. 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 
NIAAA have identified 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.



The isolation of mutant mice with altered ethanol-related behavior is a 
powerful method for identifying genes influencing ethanol-related behavior, 
in a manner unbiased by prior physiological hypotheses.  NIAAA has 
accordingly previously provided funds for this purpose to Mouse Mutagenesis 
centers at the Jackson Laboratory (  and the 
University of Tennessee at Memphis (  These 
Centers, along with a third Center at Northwestern University 
(, have begun to generate large numbers of 
chemically induced single-gene mutant mice with alterations in a wide variety 
of behaviors and nervous system functions.  The first two of these centers 
are screening for mutants with alterations in ethanol consumption, ethanol-
induced hypothermia, ataxia, locomotor activation, and anxiolysis.  Mutants 
isolated in these screens will be tested to determine whether they also 
display alterations in the temporal structure of their drinking behavior 
(measured with a lickometer), as well as their ethanol-induced sedation, 
conditioned taste aversion, and operant self-administration.  These centers 
are also screening for mutants with altered sensorimotor gating, anxiety, 
novelty-seeking, aggression, and responses to other drugs of abuse, all of 
which traits may be mechanistically related to various types of ethanol-
related behavior.  All of these mutants will be made available to the general 
research community for further intensive study.  

The underlying purpose of creation of mutants with altered behavioral 
responses to ethanol is the elucidation of the physiological mechanisms 
mediating such responses.  Creation of mutants is thus not an end in itself, 
but is rather the starting point of such investigation.  One informative path 
for such investigation is the identification of the mutated genes responsible 
for the behavioral alterations.  Some of these genes may encode proteins of 
previously known function, which have not previously been suspected of 
mediating ethanol-related behavior.  In such a case, identification of the 
mutated gene may immediately draw attention to the entire biochemical pathway 
in which the encoded protein functions.  In cases where this pathway is not 
known, the identity of the mutated gene can be the starting point for the 
elaboration of such a pathway.  Such elaboration requires further 
neuroanatomical, neuropharmacological, and neurophysiological analyses of the 
mutant mice to determine the sequence of physiological alterations linking 
the mutated gene with the mutant's altered behavioral responses to ethanol.  
Comparison of global patterns of gene expression in the nervous systems of 
either naive or ethanol-exposed mutant and wild-type mice can also help 
elucidate the physiological changes linking the mutation with the behavioral 
changes it entrains.  This RFA is soliciting proposals employing any current 
methodology to reveal the causal chain of events linking mutation with 
altered behavior.

Although the mutagenesis centers are screening for mutants with alterations 
in a range of ethanol-related behaviors (listed above), mutant mice with 
alterations in more complex neuroadaptive responses to ethanol would also be 
desirable tools for elucidating the physiological mechanisms of these 
adaptations.  Such adaptations include sensitization, tolerance (physical and 
motivational), dependence, withdrawal (physical and affective aspects), 
deprivation- or stress-induced consumption, initiation of consumption, 
reinforcement, and ethanol discrimination. Mutants with altered nervous 
system responses to ethanol (such as levels of hormones, neuropeptides, or 
neurotransmitter metabolites in cerebrospinal fluid) would be of similar 
value to the research community.  NIAAA encourages investigators inclined to 
develop high-throughput assays of nervous system and behavioral responses to 
ethanol to respond to this RFA with proposals for mutant screens employing 
such assays.

Collaborations with Established Mutagenesis Centers

Applications for studies on existing mutant mice must document either the 
actual presence of the animals in the investigator's laboratory, or provide a 
letter from the supplying facility specifying when the mutants will be 
shipped to the investigator's laboratory. For access to these mutants, 
investigators should consult the websites of the mutagenesis centers (listed 
under Background,  above).  In addition, mutant mice will be available from a 
distribution facility operated under contract to NIH, solicited under request 
for proposals RFP NIMH-01-DN-0018, "Mouse Neuroscience Phenotyping and 
Distributing Center".  Once this facility is operational, contact information 
about it will be posted on the Trans-NIH Mouse Initiative webpage,

Investigators wishing to screen for new mutants should establish a 
collaboration with an existing Mouse Mutagenesis Center, either one of those 
mentioned under Background (above), or some other such Center.  Potential 
applicants are encouraged to contact NIAAA Program Staff (see INQUIRIES, 
below) for more information about existing Mouse Mutagenesis Centers.  
Investigators may arrange to screen mice on-site at a Mutagenesis Center 
(under the Center's Visiting Investigator Program), or may have mutant mice 
shipped from the Center to their own laboratories for screening.  
Applications must document the collaboration in detail, clearly specifying 
the respective roles of the investigator and any staff of the Mutagenesis 
Center.  In addition, applicants who receive animals are responsible for all 
shipping and handling costs, and must provide for the care and welfare of 
these animals in accordance with all Federal, state and local laws.  
Applications to set up new mouse mutagenesis facilities will not be 
considered responsive to this RFA.

Areas of Interest

The following examples of projects supportable under this RFA are for 
illustration only, and are not exclusive.
- Mapping and identification of the genes mutated in existing mutant mice.
- Characterization of complex ethanol-related behavior of existing mutants, 
e.g., ethanol sensitization, tolerance (physical or motivational), 
dependence, withdrawal (physical or affective aspects), deprivation- or 
stress-induced consumption, initiation of consumption, reinforcement, ethanol 
- Identification of neuroanatomical, neurochemical, or neurophysiological 
mechanisms mediating alterations of ethanol-related behavior in existing 
mutants (e.g., changes in synaptic connectivity or morphology, receptor 
density or activity, neurotransmitter synthesis or release, spontaneous or 
evoked neuronal firing, protein kinase localization and activity, receptor 
phosphorylation state).
- Analysis of altered patterns of gene or protein expression in the nervous 
system of existing mutants, which could mediate their alterations in ethanol-
related behavior.
- High-throughput screens for new mutants with altered complex ethanol-
related behavior, or altered nervous-system responses to ethanol.


Sharing of Materials Generated Under this RFA and Exercise of Intellectual 
Property Rights 

Projects funded under this RFA are likely to lead to the creation of new 
mutant mice and new genetic stocks containing previously existing mutations, 
as well as other research tools of great value to the broader research 
community.  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 
generated through the grant.  Resources to be shared should include all 
materials developed in projects funded under the RFA, including but not 
limited to, mutant animals, preserved embryos and sperm, phenotypic and 
genetic data, phenotyping assays, and instrumentation.  For this purpose, 
NIAAA views the dissemination of such resources through individual 
laboratories and websites is not sufficient, since it would force interested 
investigators to search numerous websites in order to gain access to research 
tools generated under this RFA. It is preferable that materials generated 
under this RFA be placed in common, public repositories and databases that 
are widely accessible by investigators in the scientific community.  The 
investigator's resource sharing plan should include a description of the 
mechanisms proposed for wide distribution of resources with investigators in 
the scientific community, and a timetable for such distribution. 

Mutant mice developed by the mutagenesis centers funded under RFA MH-99-007 
(the Jackson Laboratory, University of Tennessee at Memphis, Northwestern 
University) and RFA HD-99-007 (Baylor College of Medicine) are covered by a 
Declaration of Exceptional Circumstances (DEC) to the Bayh-Dole Act, 37 
C.F.R. 401.3(a)(2), which prohibits patenting thereof.  Any mutant stocks 
developed elsewhere are not covered by this DEC.  With regard to such mutant 
stocks and other patentable research materials, such as phenotyping assays, 
protocols, instrumentation, and methodologies, NIAAA requires applicants who 
respond to this RFA to propose a plan addressing whether, and how, they will 
exercise their intellectual property rights while making available to the 
broader scientific community research resources produced in
projects funded under this RFA.  This plan should include a description of 
the applicant's plans to generate, or not generate, patents and/or exclusive 
or non-exclusive licensing of biomaterials and other patentable subject 
matter created in projects funded under this RFA.  This plan is also expected 
to include disclosure of any pre-existing intellectual property rights, 
including options to for-profit research sponsors, that are associated with 
biomaterials and data that may be generated.   This plan for exercise of 
intellectual property rights is required in addition to the plan for sharing 
and disseminating research resources (described above).

The reviewers will make an administrative comment on the adequacy of the 
proposed plans for resource sharing and exercise of intellectual property 
rights. (This comment will not affect the priority score of the proposal.)  
NIAAA program staff will consider the adequacy of these plans in determining 
whether to recommend an application for award. These plans 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,"

Evaluation of any future renewal applications will include assessment of the 
awardee's adherence to the proposed plan.  Applicants are also reminded that 
the grantee institution is required to disclose each subject invention to NIH 
within two months after the inventor discloses it in writing to grantee 
institution personnel responsible for patent matters.  NIAAA reserves the 
right to monitor awardee activity in this area to ascertain if patents or 
patent applications on phenotyping assays, protocols, instrumentation, 
methodologies or other patentable subject matter are adversely affecting the 
goals of this RFA.


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.


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:

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.


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 IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to 

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) 
Telephone:  (301) 443-4375
FAX:  (301) 443-6077 

by the letter of intent receipt date listed.


The PHS 398 research grant application instructions and forms (rev. 5/2001) 
available at must be 
used in applying for these grants. This version of the PHS 398 is available 
in an interactive, searchable format.  For further assistance contact 
GrantsInfo, 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 NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at must be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

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:

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:

Extramural Project Review Branch
Attn: AA-02-007 
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) 

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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIAAA.  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?

(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 

(6) For applications proposing to screen for new mutants, are the proposed 
screens likely to lead to the isolation of mutant mice which will be useful 
to the research community for investigating the mechanisms of uncontrolled 
ethanol consumption and ethanol dependence? 

(7) Will the mutants be bred into genetic stocks which will be convenient for 
the research community to use?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the reasonableness of the 
proposed budget and duration in relation to the proposed research.  The 
reviewers will also be asked to comment administratively on the adequacy of 
the resource sharing and intellectual property plans, but these comments will 
not affect the score of the application.


Letter of Intent Receipt Date:    March 15, 2002
Application Receipt Date:         April 15, 2002
Peer Review Date:                 June-July 2002
Council Review:                   August 2002
Earliest Anticipated Start Date:  September 28, 2002


Award criteria that will be used to make award decisions include:
- scientific merit (as determined by peer review)
- availability of funds
- programmatic priorities
- For applications proposing to screen for new mutants, how well the proposed 
screens complement ongoing screens already funded by NIAAA.
- Adequacy of the proposed plans for resource sharing and exercise of 
intellectual property rights.


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:

Lisa Neuhold, Ph.D.
Neurosciences and Behavioral Research Branch
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20850 (for express/courier service)
Telephone:  (301) 594-6228
FAX:  (301) 594-0673

Antonio Noronha, Ph.D.
Chief, Neurosciences and Behavioral Research Branch
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20850 (for express/courier service)
Telephone:  (301) 443-7722
FAX:  (301) 594-0673

Direct inquiries regarding fiscal matters to:

Ms. Judy Simons
Grants Management Branch 
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Blvd, Suite 504, MCS 7003 
Bethesda, MD  20892-7003 
Telephone:  (301) 443-2434
FAX:  (301) 480-3891 


This program is described in the Catalog of Federal Domestic Assistance No. 
93.273.  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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