mRNA PROFILING OF THE MAJOR MENTAL DISORDERS: EXPLOITING POSTMORTEM HUMAN TISSUE 
THROUGH GENE ARRAY TECHNOLOGY

RELEASE DATE:  June 1, 2004

RFA NUMBER:  RFA-MH-05-005  

EXPIRATION DATE:  August 18, 2004

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.242

LETTER OF INTENT RECEIPT DATE:  July 19, 2004
APPLICATION RECEIPT DATE:  August 17, 2004  

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  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
o  Supplementary Instructions
o  Peer Review Process
o  Review Criteria
o  Receipt and Review Schedule
o  Award Criteria
o  Required Federal Citations

PURPOSE OF THIS RFA 

This RFA seeks applications that will foster analysis of mRNA profiling in the 
major mental disorders.  Specifically, the initiative will provide support for 
investigators who wish to initiate or expand their use of gene array profiling 
technology in studies of human postmortem brain tissue.  It is anticipated that 
such efforts will expand the available data on psychiatric disease-specific mRNA 
profiles and simultaneously encourage related experiments to understand the 
neural basis of abnormal gene expression profiles.

RESEARCH OBJECTIVES

Routine interrogation of the human genome is an emerging research approach in 
both basic and clinical settings.  Current technology to assess genes, their 
transcriptomes and proteomes is maturing rapidly.  In particular, microarray 
methodologies, despite some limitations, can be used to determine genetic 
differences between pathological and normal biological samples.  Microarrays can 
be used to evaluate either variation in gene expression (mRNA profiling), or 
variation in DNA sequence (gene profiling).  Schizophrenia, major depression, 
bipolar disorder, and other major mental disorders are complex diseases 
characterized as genetically polymorphic (high allelic variation).  Efforts to 
identify DNA polymorphisms in these diseases (disease haplotypes) are underway, 
but will require some time for success.  mRNA profiling in postmortem human 
brain may be a more rapid approach to discerning pathophysiological “leads.”  
With microarray technology, investigators can generate data on brain expression 
phenotypes using both regional and cellular gene expression patterns.  Although 
such patterns may, or may not, be directly related to causative genetic factors, 
they are likely to be associated with pathophysiology and neural abnormalities.  
Comprehensive mapping of disease-specific brain gene expression phenotypes could 
then provide a path of entry into analysis of brain mechanisms that are directly 
responsible for disease symptoms.  These mechanisms are promising substrates for 
the development of novel treatments and interventions.

MECHANISM(S) OF SUPPORT

This RFA will use NIH Research Project Grant (R01) and Exploratory/Developmental 
Grant (R21) award mechanisms.  As an applicant, you will be solely responsible 
for planning, directing, and executing proposed projects.  The R21 mechanism 
(see https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) 
is intended to encourage new exploratory/developmental research projects by 
providing support for the early stages of their development.  For example, such 
projects could assess the feasibility of a novel area of investigation or a new 
experimental system that has the potential to enhance health-related research.  
These studies may involve considerable risk but may lead to a breakthrough in a 
particular area, or to the development of novel techniques, agents, 
methodologies, models or applications that could have a major impact on a field 
of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those 
supported through the traditional R01 mechanism.  For example, long-term 
projects, or projects designed to increase knowledge in a well-established area 
will not be considered for R21 awards.  Applications submitted under this 
mechanism should be exploratory and novel.  These studies should break new 
ground or extend previous discoveries toward new directions or applications.

R21 applications may request a project period of up to two years with a combined 
budget for direct costs of up $275,000 for the two-year period.  For example, 
you may request $100,000 in the first year and $175,000 in the second year.  The 
request should be tailored to the needs of your project.  Normally, no more than 
$200,000 may be requested in any single year.

R01 applications may request a project period of up to five years and a budget 
for direct costs of up to $250,000 per year.

This RFA is a one-time solicitation.  Future unsolicited, competing-continuation 
applications based on this request will compete with all other investigator-
initiated applications and will be reviewed according to the customary peer review 
procedures.  The anticipated award date is April 2005.  Applications that are not 
funded in the competition described in this RFA may be resubmitted as NEW 
investigator-initiated applications using the standard receipt dates for NEW 
applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts.  It also uses the modular budgeting 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 $250,000 or less, 
use the modular budget format.  Otherwise follow the instructions for non-modular 
budget research grant applications.  This program does not require cost sharing as 
defined in the current NIH Grants Policy Statement at 
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.

FUNDS AVAILABLE

The NIMH intends to commit approximately $1,000,000 total costs in 2005 to fund up 
to 5 new and/or competitive continuation grants in response to this RFA.     
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 NIMH 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.

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the following 
characteristics:

o  For-profit or non-profit organizations
o  Public or private institutions, such as universities, colleges, hospitals, and 
laboratories
o  Units of State and local governments
o  Eligible agencies of the Federal government
o  Domestic or foreign institutions/organizations
o  Faith-based or community-based organizations

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.

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:

Douglas L. Meinecke, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7179, MSC 9639
Bethesda, MD  20892-9639
Telephone:  (301) 443-1692
FAX:  301-402-4740
Email:  dmeineck@mail.nih.gov

o  Direct your questions about peer review issues to:

Michael Kozak, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9608
Bethesda, MD  20892-9608
Rockville, MD  20852-9608 (for express/courier service)
Telephone:  (301) 443-1340
FAX:  (301) 443-4720
Email:  kozakm@mail.nih.gov

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

Carol J. Robinson
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6118
Bethesda, MD  20892
Telephone:  (301) 443-3858
FAX:  (301) 443-6885
Email:  crobinso@mail.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 NIMH 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:

Douglas L. Meinecke, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7179, MSC 9639
Bethesda, MD  20892-9639
Telephone:  (301) 443-1692
FAX:  301-402-4740
Email:  dmeineck@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a DUN and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier 
when applying for Federal grants or cooperative agreements.  The DUNS number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/.  The DUNS number should be entered on line 11 of 
the face page of the PHS 398 form.  The PHS 398 document 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.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications requesting up 
to $250,000 per year in direct costs must be submitted in a modular grant format.  
The modular grant format simplifies the preparation of the budget in these 
applications by limiting the level of budgetary detail.  Applicants request direct 
costs in $25,000 modules.  Section C of the research grant application instructions 
for the PHS 398 (rev. 5/2001) at 
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/labels.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 and all copies 
of the appendix material must be sent to:

Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9663
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-3367
FAX:  (303) 443-4720
Email:  jnoronha@mail.nih.gov

APPLICATION PROCESSING:  Applications must be received on or before 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.

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.

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.  However, when a previously 
unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared as a 
NEW application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must not be 
marked to indicate the changes from the previous unfunded version of the 
application.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIMH.  Incomplete and/or nonresponsive applications will not 
be reviewed.  

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 
NIMH in accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will:

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 written critique
o  Receive a second level review by the National Advisory Mental Health 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 evaluate the application in order to judge the 
likelihood that the proposed research will have a substantial impact on the pursuit 
of these goals.  The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, weighting them as 
appropriate for each application.

o  Significance
o  Approach
o  Innovation
o  Investigator
o  Environment

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.

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?

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?

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?

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)?

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?  

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the following items 
will be considered in the determination of scientific merit and the priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human subjects 
and protections from research risk relating to their participation in the proposed 
research will be assessed. (See criteria included in the section on Federal 
Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  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 in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    July 19, 2004
Application Receipt Date:         August 17, 2004
Peer Review Date:                 Oct/Nov 2004
Council Review:                   January 2005
Earliest Anticipated Start Date:  April 2005

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 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities involving 
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of 
Laboratory Animals 
(https://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated 
by the Health Research Extension Act of 1985 
(https://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal 
Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as 
applicable.

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that applications 
and proposals involving human subjects must be evaluated with reference to the 
risks to the subjects, the adequacy of protection against these risks, the 
potential benefits of the research to the subjects and others, and the importance 
of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

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 "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.  

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.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to the 
“Standards for Privacy of Individually Identifiable Health Information”, the 
“Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal regulation under 
the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that 
governs the protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside with 
the researcher and his/her institution.  The OCR website (http://www.hhs.gov/ocr/) 
provides information on the Privacy Rule, including a complete Regulation Text and 
a set of decision tools on “Am I a covered entity?”  Information on the impact of 
the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts can be found 
at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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.healthypeople.gov/.

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review.  Awards are made under the authorization of Sections 301 and 405 of 
the Public Health Service Act as amended (42 USC 241 and 284and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All awards are subject to the 
terms and conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be found at 
https://grants.nih.gov/grants/policy/policy.htm.

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.

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