NOVEL GENETIC METHODS TO MAP FUNCTIONAL NEURONAL CIRCUITS AND SYNAPTIC CHANGE

RELEASE DATE:  October 10, 2002

PA NUMBER:  PAR-03-007 (see change NOT-DA-04-003)

APPLICATION RECEIPT DATE:  The receipt dates for this Program Announcement 
are: February 12, 2003, February 12, 2004, and February 14, 2005.

National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov)
National Institute of Alcohol Abuse and Alcoholism (NIAAA) 
 (http://www.niaaa.nih.gov)
National Institute on Deafness and Other Communication Disorders (NIDCD)
 (http://www.nidcd.nih.gov)
National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) 
 (http://www.niddk.nih.gov)
National Eye Institute (NEI) 
 (http://www.nei.nih.gov)
National Institute of Mental Health (NIMH) 
 (http://www.nimh.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov)

THIS PROGRAM ANNOUNCEMENT (PA) CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

This PA solicits applications to develop new genetic-based methods and 
technologies for the purpose of mapping functional neuronal circuits and 
synaptic changes in the mammalian nervous system. Emerging genetic and 
transgenic technologies can be used to single out functionally related cells 
or neuronal populations for analysis or intervention. This PA would support 
the development of genetic-based tools to map neuronal interconnectivity, to 
monitor functional changes, or to drive functional changes within neuronal 
circuits as the first step in an effort by the NIH to create integrated 
genomic and functional connectivity maps of the mammalian nervous system. 
Other corollary efforts needed to generate integrated connectivity maps such 
as improved neuroinformatics and the development of a large consortia of 
investigators, however, are outside the scope of this program announcement.  

Wide distribution to the scientific community of the methods and resulting 
resources developed under this program is essential for the eventual goal of 
creating large-scale functional connectivity maps of the mammalian nervous 
system. The unrestricted distribution of methods and resources developed 
under this program will also facilitate the rapid transfer of technology for 
the development of diagnostic tools and treatment interventions for brain 
disease.  

RESEARCH OBJECTIVES

Background

In January 2002, the National Institute of Mental Health (NIMH), the National 
Institute on Drug Abuse (NIDA), and the National Institute of Neurological 
Disorders and Stroke (NINDS) held a meeting at Laguna Beach, California, on 
"Setting Priorities for Functional Molecular Neuroanatomy in the Post-Genomic 
Era" http://trans.nih.gov/bmap/reports/reports.htm.  One of the major 
recommendations from the meeting is for the National Institutes of Health 
(NIH) to develop initiatives directed toward mapping the functional neuronal 
circuits and plastic changes in the brain using powerful new genetic-based 
strategies. Highest priority was given to mapping functional circuits in the 
mouse and other mammalian systems that are amenable to genetic manipulation 
and intervention. It was recognized that an important first step toward this 
goal is the further development of genetic-based methods and technologies for 
this purpose.

Understanding the pattern of interconnections of specific neural cells is 
essential to understanding their roles in nervous system function and 
dysfunction. Traditionally, the connections a neuron makes have been 
identified using electrophysiological recordings, from histochemical 
techniques or through the use of anterograde or retrograde tracers that make 
it possible to visualize the patterns of projections of individual neurons.  
While these approaches have been useful to identify certain aspects of neural 
connectivity, their utility is limited by their invasiveness, unavoidable 
confounding artifacts, and the inability to reproduce findings with great 
fidelity. 

Methods for mapping functional activity in neuronal circuits also suffer 
limitations, particularly with respect to resolution in space and time. For 
example, Positron Emission Tomographic imaging using radioactive deoxyglucose 
is limited in both temporal and spatial resolution. The use of early 
immediate genes, such as fos, to detect neuronal activity has high cellular 
resolution but the temporal resolution of this method is limited. Magnetic 
Resonance Imaging (MRI), on the other hand, reveals the activation of 
specific brain areas but does not permit an analysis of functionally 
interconnected neuronal circuits, and the relationship between MRI-detected 
activation and neuronal activity is not well understood.

Other technologies used to study functional activity, such as voltage 
sensitive dyes and calcium indicators, provide good temporal and spatial 
resolution, but also pose technical obstacles. These include toxicity, lack 
of dye penetration into the cells of interest, and chemical degradation of 
the dye once inside the cell.  

Current methods for manipulating activity in neuronal circuits are crude. 
These include electrolytic or mechanical lesions, microinjection of 
tetrodotoxin or other neurotoxic agents into target areas, and the local 
administration of anesthetics or other pharmacologic agents. Many of these 
manipulations, however, are not reversible, difficult to control, and 
frequently disrupt more than one neuronal circuit.

Despite the importance that plasticity plays in brain function, dysfunction, 
and recovery from injury, existing methods do not permit the visualization of 
dynamic or fluctuating changes at central synapses that may occur over 
prolonged time periods or the altered network properties that accompany 
learning and memory; nor do methods exist to image dynamic changes between 
neuronal connections during development, learning, aging, adaptation to 
chronic exposure to drugs, etc. Thus, new methods are needed if the process 
of plasticity is to be better understood at all levels of organization, from 
the subcellular to the systems level. 

Powerful new genetic approaches offer new opportunities to overcome many of 
the obstacles described or alluded to above. For example, subpopulations of 
neurons are increasingly being distinguished based on their pattern of gene 
expression. Cell-type specific promoters, therefore, allow the isolation of 
functionally related cells or neuronal populations, and can be used to trace 
the connections of these cells by driving the expression of genetically-
encoded markers of neural connectivity (e.g., green fluorescent protein and 
its variants). Much effort is currently being devoted to devising 
genetically-encoded tracers that are transported across synapses and thus 
permit transsynaptic tracing of connections, both anterogradely and 
retrogradely, allowing extended, multisynaptic patterns of neural 
connectivity to be defined. Other studies have suggested the feasibility of 
using virus-assisted mapping of neuronal circuits that can be activated by 
focal injections of a catalyst or by electromagnetic radiation. A powerful 
variation on this theme is the recent development of a recombinant viral 
vector that is dependent on a Cre recombinase for replication and for 
expression of a genetically-encoded reporter. Potentially even more powerful 
are genetically-encoded reporters that can be used to monitor neural 
activity, the activity of signal transduction pathways, transmitter release, 
or other functional changes within neurons (e.g., Clomeleon, FlaSH, cameleons 
and synapto-pHluorins using optical or FRET-based approaches). Technologies 
like these have the potential to dramatically facilitate the mapping of 
functional neuronal circuits in the complex environment of the brain. 

Recent studies also suggest that genetic approaches can be used to alter or 
drive patterns of neural activity or signaling responses in defined neuronal 
populations. Transfection of neurons with the phototransduction apparatus has 
been shown to confer white light responsiveness within selected groups of 
neurons. This has worked in vitro but has not yet been tested in vivo. The 
ability to successfully activate selected neurons and their neural circuits 
in vivo in response to penetrating radio waves, light, or a magnetic field 
would be a very powerful technology for understanding the function of these 
selected neurons and neural circuits in the awake behaving animal.

The primary goal of this program announcement, then, is to support the 
development of novel (or significantly improve existing) genetic-based 
methods and technologies for the purpose of mapping functional neuronal 
circuits and synaptic changes in the mammalian nervous system. 

The R21 mechanism is intended for feasibility studies while the R01 mechanism 
is intended for the development and initial application of these methods to 
mammalian model systems. 

Research Scope

The types of projects supported by this initiative include but are not 
limited to: 

o  Development of cell-type specific promoters or improvement of BAC 
technology to specifically label or isolate distinct neuronal classes and 
their projections for the purpose of mapping functional neuronal circuits 
(e.g., Fugu promoters, BAC clones to drive cell-specific expression of 
markers or reporters);

o  Development or improvement of genetic-based methods to map neuronal 
circuits and identify the afferents and efferents of defined neuronal 
populations including complex patterns of interconnectivity (e.g., using 
optical indicators or other genetically-encoded reporters coupled to a cell-
type specific promoter);

o  Methods for detecting electrical activity in mammalian neurons by optical 
recording from genetically-encoded reporters (e.g., membrane potential 
sensors, calcium indicators, etc.);

o  Methods for detecting neuronal activity in deep brain structures using 
genetically-encoded reporters particularly suited for in vivo applications 
(e.g., caged contrast agents for magnetic resonance imaging, expression of 
bacterial genes involved in magnetic particle synthesis); 

o  Methods for visualizing the activity of signal transduction pathways in 
neurons and neuronal circuits using genetically-encoded reporters or other 
fusion constructs (e.g., using FRET-based or other optical technologies);

o  Genetic-based methods for the persistent labeling of neurons over 
prolonged periods of time in order to follow plastic changes in morphology, 
connections or function;

o  Genetic-based methods for visualizing dynamic changes in neuronal 
connections, such as pulse-chase labeling of synapses (e.g., using different 
colors of fluorophores to label older and younger protein molecules);

o  Methods to correlate the genetic expression profile of a cell or defined 
neuronal population with its pattern of neuronal activity and neuronal 
interconnectivity; or conversely, to develop better in vivo methods for 
detecting alterations in gene expression that are induced by neural activity 
or other means; 

o  Genetic-based methods for controlling or driving neural activity or 
signaling responses in defined neuronal populations (e.g., using genetically-
encoded modulators of electrical activity that can be activated by specific 
signals such as pharmacological agents or light).

MECHANISMS OF SUPPORT

This PA will use the NIH research project grant (R01) and 
exploratory/developmental grant (R21) award mechanisms.      
The R21 mechanism is intended to encourage exploratory research projects 
where sound methodology and strong rationales exist, but for which 
preliminary data do not.  Applicants should note that the R21 grant is 
limited to $100,000 for direct costs (including facilities and administrative 
costs on consortium arrangements, if any) per year up to three years. 
The R01 mechanism should be used in cases where the applicant has developed a 
body of preliminary data or previous methods or technology upon which the 
application will build.  

Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant. This PA is a three-time 
solicitation.  Competing continuation applications if submitted in response 
to this PA, will compete with all investigator-initiated applications and be 
referred and reviewed according to the customary peer review procedures.  The 
earliest anticipated award date is September 30, 2003.

FUNDS AVAILABLE

The participating institutes will commit a minimum of $1,100,000 in total 
costs [direct plus Facilities and Administrative (F & A) costs] in FY 2003 to 
fund 5 to 6 new grants in response to this PA.  Applicants may use the 
dollars available and anticipated number of awards as a guide to develop 
reasonable budgets for their research projects.  For an 
exploratory/development grant (R21), an applicant may request a budget for 
direct costs of up to $100,000 per year, including F & A costs on consortium 
arrangements for up to three years.

This PA uses just-in-time concepts.  It also uses the modular and 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 format.

Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of awards also will vary. Although the financial 
plans of the participating institutes provide support for this program, 
awards pursuant to this PA 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
o Foreign

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

Restricted availability of unique research resources upon which further 
studies are dependent can impede the advancement of research and delivery of 
medical care. The sharing of biomaterials, data, and software in a timely 
manner, on the other hand, has been an essential element in the rapid 
progress that has been made in the genetic analysis of mammalian genomes. NIH 
policy requires investigators to make unique research resources readily 
available for research purposes to qualified individuals within the 
scientific community when they have been published [NIH Grants Policy 
Statement (https://grants.nih.gov/grants/policy/nihgps/); Principles and 
Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining 
and Disseminating Biomedical Research Resources:  Final Notice, December 1999 
(http://www.nih.gov/od/ott/RTguide_final.html)]. Biomaterials and other 
patentable research resources (e.g., genetically encoded reporters, vectors, 
embryonic cell lines, etc.) produced in projects funded by this PA are 
expected to be made available and distributed to the broader scientific 
community.

The NIH is interested in ensuring that the research resources developed 
through this PA become readily available to the research community for 
further research, development, and application, in the expectation that this 
will lead to products and knowledge of benefit to the public. For this 
reason, NIH is concerned that patents on the vectors, mutagenesis methods, 
cell lines, and other research resources might have a chilling effect on the 
future development of products and information that may improve the public 
health. At the same time, NIH recognizes the rights of grantees to elect and 
retain title to subject inventions developed under federal funding under the 
provision of the Bayh-Dole Act.  There are two special requirements for this 
PA regarding research resources produced in proposed projects:

(1)  Applicants are required to include in their application a specific plan 
by which they will share research resources with the wider scientific 
community. 

(2)  Applicants are required to include a plan addressing if, or how, they 
will exercise their intellectual property rights while making available to 
the broader scientific community patentable research resources. These plans 
should be consistent with the policies of their institutional offices of 
technology transfer.

Applicants are encouraged to discuss their proposed plans for addressing 
these requirements with their institutional offices of technology transfer. 
Each of the two requirements is discussed in detail below. 

Plan to Share Research Resources 

To address the joint interests of the government in the availability of, and 
access to, the results of publicly funded research, NIH requires applicants, 
who respond to this PA to propose detailed plans for sharing the research 
resources generated through the grant. It is expected that the resources to 
be shared include all materials developed in projects funded under the PA. A 
reasonable time frame for release of materials should be specified in the 
application and will be considered during the review of the plan for sharing.

It is expected that the investigator's data and biomaterials sharing plan 
will include the access to biomaterials and methods not currently available 
to the wider scientific community. It is also expected that the 
investigator's data, papers, and biomaterials will be linked to the Brain 
Molecular Anatomy Project (BMAP) web page http://trans.nih.gov/bmap/.

The scientific review group will evaluate the adequacy of the proposed plan 
for sharing and data access. Comments on the plan and any concerns will be 
presented in an administrative note in the Summary Statement. The adequacy of 
the plan will be considered by NIH program staff and will be important in 
determining whether the grant shall be awarded. The sharing plan approved by 
program staff, after negotiation with the applicant when necessary, will 
become part of the terms and conditions of the award. NIH program staff will 
evaluate the compliance with the sharing plan and scientific progress in the 
non-competing continuation of the grant award application.
 
Intellectual Property Rights 

NIH is interested in ensuring that the research resources developed through 
this PA become readily available to the research community.

With regard to patentable research results, such as genetically encoded 
reporters, cell lines, and vectors, the NIH requires applicants who respond 
to this PA to develop a plan addressing if, or how, they will exercise their 
intellectual property rights while making available to the broader scientific 
community research resources produced in projects funded under this PA. This 
is expected to include an elaboration of the applicant's anticipated 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 PA. This plan should be consistent with the 
applicant's institution's policies on intellectual property rights. 

This plan is also expected to include disclosure of any pre-existing 
agreements involving intellectual property rights, including options to for-
profit research sponsors that are associated with biomaterials and data that 
may be generated. The requirement for this plan is in addition to the 
requirement for the plan for sharing and disseminating research resources 
described in the previous section. 

The majority of transfers to not-for-profit entities should be implemented 
under terms no more restrictive than the Uniform Biological Materials 
Transfer Agreement (UBMTA). In particular, recipients are expected to use the 
Simple Letter Agreement provided at 
http://www.nih.gov/od/ott/RTguide_final.htm, or another document with no more 
restrictive terms, to readily transfer unpatented tools developed with NIH 
funds to other recipients for use in NIH-funded projects. If the materials 
are patented or licensed to an exclusive provider, other arrangements may be 
used, but commercialization option rights, royalty reach-through, or product 
reach-through rights back to the provider are inappropriate. 

Similarly, when for-profit entities are seeking access to NIH-funded tools 
for internal use purposes, recipients should ensure that the tools are 
transferred with the fewest encumbrances possible. The Simple Letter 
Agreement may be expanded for use in transferring tools to for-profit 
entities, or simple internal use license agreements with execution or annual 
use fees may be appropriate.

The scientific review group will evaluate the adequacy of the proposed plan 
for handling intellectual property rights. Comments on the plan and any 
concerns will be presented in an administrative note in the Summary 
Statement. NIH program staff in determining whether the grant shall be 
awarded will consider the adequacy of the proposed plan. The plan as 
approved, after negotiation with the applicant when necessary, will be a 
condition of the award. Evaluation of non-competing continuation applications 
will include assessment of the awardee's adherence to the proposed plan.  

Applicants also are 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 institutional personnel responsible for 
patent matters. The awarding institute reserves the right to monitor awardee 
activity in this area to ascertain if patents or patent applications on 
mutagenesis protocols, cell lines, vectors, or other patentable subject 
matter are adversely affecting the goals of this PA.

Principles and guidelines for recipients of NIH research awards on obtaining 
and disseminating biomedical research resources can be found at 
http://www.nih.gov/od/ott/RTguide_final.htm.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants. Inquiries may fall into two 
areas:  scientific or research, and financial or grants management issues:

o Direct your questions about scientific and research issues to:

Dr. Jonathan Pollock
National Institute on Drug Abuse 
6001 Executive Boulevard, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-6300
Email:  jpollock@mail.nih.gov

Dr. Bradley C. Wise
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307 MSC 9205
Bethesda, MD   20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email:  wiseb@nia.nih.gov 

Dr. Lisa A. Neuhold
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

Dr. Lynn Luethke
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, MSC 7180
Bethesda, MD 20892-7180
Telephone: 301-402-3458
Email: luethkel@mail.nih.gov

Dr. Philip Smith
National Institute of Diabetes and Digestive and Kidney Diseases 
2 Democracy Plaza
Bethesda, MD 20892
Telephone: 301-594-8816
Email:  SmithP@ep.niddk.nih.gov

Dr. Michael D. Oberdorfer
National Eye Institute
6120 Executive Boulevard
Bethesda, MD 20892
Telephone: 301-451-2020
Email: mdo@eps.nei.nih.gov

Dr. Michael F. Huerta
National Institute of Mental Health
6001 Executive Boulevard, Room 7202, MSC 9645
Rockville, MD 20852-9645
Telephone: (301) 443-3563
Fax: (301) 443-1731
Email:  mhuerta@helix.nih.gov

Dr. Laura A. Mamounas
National Institute of Neurological Disorders and Stroke (NINDS)
Neuroscience Center, Room 2206, MSC 9525
6001 Executive Boulevard, MSC 9525
Bethesda, MD  20892-9525
(courier: Rockville, MD  20852-9525)
Telephone:  (301) 496-1447
Fax:  (301) 480-1080
Email: mamounas@ninds.nih.gov

Dr. Mary Lou Oster-Granite
Health Scientist Administrator
Mental Retardation and Developmental Disabilities Branch
Center for Research for Mothers and Children
6100 Executive Boulevard, Room 4B09D, MSC 7510
National Institute of Child Health and Human Development
Bethesda, MD 20892-7510
Telephone:  (301) 435-6866
Fax:  (301) 496-3791 
Email:  mo96o@nih.gov

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

Gary Fleming, J.D., M.A.
Grants Management Branch
Office of Planning and Resource Management
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD 20892-9541
Phone: (301) 443-6710
Fax: (301) 594-6847
Email: gf6s@nih.gov

Ms. Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  WhippL@nia.nih.gov

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

Ms. Sara Stone
Grants Management Branch
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400B
6120 Executive Boulevard, MSC-7180
Bethesda, MD 20892-7180 
Rockville, MD 20852 (express mail)
Telephone: (301) 402-0909
FAX:  (301) 402-1758
Email: stones@nidcd.nih.gov

Ms. Kieran Kelley
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Rm. 721 MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-0417 
FAX:  (301) 480-3504
E-mail:  kk27g@nih.gov

Mr. William Darby
Grants Management Officer
National Eye Institute/NIH
Executive Plaza South, Suite 350
Bethesda, MD  20892-7164
Phone: (301) 496-5884
Fax: (301) 496-9997
Email: wwd@nei.nih.gov

Ms. Carol 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

Ms. Rebecca Claycamp
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3290
Bethesda, MD 20892
Telephone: 301-496-9231
Fax: 301-402-0219
Email: rc253d@nih.gov

Ms. Mary E. Daley
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A-17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1305
FAX:  (301) 402-0915
E-mail:  md74u@nih.gov

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 Grants Info, Telephone (301) 710-0267, 
Email: GrantsInfo@nih.gov.

SUPPLEMENTAL INSTRUCTIONS:  The Research Plan for an application using the 
R21 mechanism need not include preliminary data. Figures are allowed in the 
appendix.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the three dates listed at the beginning of 
this PA.

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.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications are capped at $100,000 for R21 mechanism.  Applications 
requesting $500,000 or more in direct costs for any year must include a cover 
letter identifying the NIH staff member within one of NIH institutes or 
centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
	
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by the receipt dates 
listed at the top of this PA. The CSR will not accept any application in 
response to this PA 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 a substantial 
revision of an application already reviewed, but such application must 
include an Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines. An appropriate scientific review group 
convened by the Center for Scientific Review in accordance with the standard 
NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit. 

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
on board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. In 
the written comments, reviewers will be asked to discuss the following 
aspects of 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:

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.

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 DATA SHARING:  The adequacy of the proposed plan to share data. 

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

AWARD CRITERIA

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 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phases I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures. In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). 

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. 

HIV/AIDS COUNSELING AND TESTING POLICY FOR THE NATIONAL INSTITUTE ON DRUG 
ABUSE:  Researchers funded by NIDA who are conducting research in community 
outreach settings, clinical, hospital settings, or clinical laboratories and 
have ongoing contact with clients at risk for HIV infection, are strongly 
encouraged to provide HIV risk reduction education and counseling. HIV 
counseling should include offering HIV testing available on-site or by 
referral to other HIV testing services. Persons at risk for HIV infection 
including injecting drug users, crack cocaine users, and sexually active drug 
users and their sexual partners. For more information see 
https://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html

NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE 
ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS:  The National Advisory Council on 
Drug Abuse recognizes the importance of research involving the administration 
of drugs to human subjects and has developed guidelines relevant to such 
research. Potential applicants are encouraged to obtain and review these 
recommendations of Council before submitting an application that will 
administer compounds to human subjects. The guidelines are available on 
NIDA's Home Page at www.nida.nih.gov under the Funding, or may be obtained by 
calling (301) 443-2755.

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 PA 
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 93.866, (NIA), 93.273 (NIAAA), 93.279 (NIDA), 
93.173 (NIDCD), 93.847 (NIDDK), 93.867 (NEI), 93.242 (NIMH), 93.853 (NINDS), 
and 93.865 (NICHD), 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.

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