RELEASE DATE:  January 22, 2002

RFA:  RFA-NS-02-012


National Institute of Neurological Disorders and Stroke, NINDS

APPLICATION RECEIPT DATE:       March 26, 2002


o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to become Principal Investigators
o Special Requirements
o Where to send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


The purpose of this RFA is to encourage the use of high throughput drug 
screening and chemical genetics in Neurodegeneration research by funding the 
development of assays that may be adapted for high throughput approaches.



Recent advances in the study of neurodegenerative disease have provided 
molecular and cellular models for studying the underlying disease mechanisms. 
Many of the same models can be adapted for use in automated drug screening 
efforts. Drug screening is a potentially powerful approach to further 
elucidate disease mechanisms and to identify new treatments.

An effective strategy developed by the pharmaceutical industry to identify new 
drugs is high throughput drug screening (HTS), using robotics to 
simultaneously test thousands of distinct chemical compounds in miniaturized 
versions of disease models. HTS is also being applied in a basic research 
strategy, known as chemical genetics, to identify new components of disease 
causing pathways. Chemical compounds that inhibit or activate specific 
proteins are useful in ways that are analogous to true genetic mutations. In 
the same way that an inactivating mutation can uncover the role of a new 
molecule in a disease process, a chemical compound that inhibits the function 
of that molecule can be used to get information about its identity, its 
activity and its interacting partners.

Many of the in vitro disease models currently used to study the effects of 
specific compounds or genetic influences can be adapted to high throughput 
formats. There are a number of characteristics that make an assay suitable for 
high throughput approaches. For example, it must be possible to reduce the 
assay to a 96-well format. The assay must be robust, reproducible, and have a 
simple readout. Many different kinds of assays have these features, including 
biochemical processes, cell-based models or simple model organisms such as 
yeast or C. elegans. This RFA is intended to encourage the design and 
development of in vitro assays for neurodegeneration that may subsequently be 
adapted for high throughput approaches.

This RFA is one component of a program to stimulate the use of chemical 
genetics and high throughput drug screening in neurodegeneration research. 
Drug screens will be supported through an NINDS contract for a centralized 
high throughput screening facility that is scheduled for award in 2002. A 
synopsis of this request for proposals may be found at  
Personnel at this facility will work collaboratively with outside 
investigators to adapt neurodegeneration assays for HTS, and then use these 
assays to screen a large, diverse compound collection. The current RFA is 
intended to encourage the development of assays to be screened at the 
facility. Because the facility will adapt the assays for HTS if necessary, 
experiments proposed in response to this RFA need not include the use of 
assays in high throughput screens or even the final stages of miniaturization 
for HTS. Rather, the emphasis is on designing and validating creative 
approaches to assaying neurodegeneration that can potentially be used for 
chemical genetics and drug discovery.


Assays proposed for this initiative should represent mechanisms associated 
with neurodegenerative diseases, including Parkinson's Disease, Amyotrophic 
Lateral Sclerosis, Alzheimer's Disease and triplet repeat disorders such as 
Huntington's Disease. 

Assays may involve proteins, cells or model organisms. However, it should be 
feasible to use the assay in an automated, high throughput screening approach. 
To allow maximum flexibility in the kinds of assays tested at the NINDS HTS 
facility, the facility will have the capacity to screen assays in what is 
considered moderate throughput by current industry criteria. Assays that 
cannot be scaled below the 96-well format will be acceptable for screening at 
the NINDS facility. Thus, an assay need not be adaptable to ultra high 
throughput format to be appropriate for this announcement. Appropriate 
assays include:

o  Toxicity of disease-causing proteins in neuronal cell lines or primary 
neuronal cultures.

o  Toxicity of disease-causing proteins in yeast or other model organisms.

o  Modulation of expression of disease-causing or neuroprotective genes, 
including effects on transcription, translation or splicing.

o  Cell-based assays of activity, processing or turnover of disease-causing or 
neuroprotective proteins. 

o  Biochemical assays of activity of disease-causing or neuroprotective proteins.

Because protein aggregation is already an active area for assay development, 
aggregation assays are not strongly encouraged unless the proposal includes a 
novel element, such as demonstration of a causal relationship between the 
state of aggregation and pathogenesis. 

Proposals should include plans to develop and validate an assay to the point 
where it appears feasible to adapt the assay for automated screening through 
further collaboration with the NINDS or another HTS facility. Demonstration of 
feasibility for eventual HTS may include:

o  Demonstration of highly predictable and reproducible response to 
pharmacological standards.

o  Demonstrated selectivity and reproducibility of response to a small but 
diverse collection of compounds, such as a collection of FDA approved drugs.

o  The availability of reliable secondary screens to evaluate the significance 
of compounds identified in the primary high throughput assay.

Use of the assay for high throughput screening need not be an aim of the 
proposal, but as discussed in the SPECIAL REQUIREMENTS section below, plans 
for screening the assay and validating the results of the screen should 
be described.


This RFA will use the National Institutes of Health (NIH) R21 award mechanism.  
Specific modifications to the application instructions, detailed below, 
reflect the nature of this mechanism and the purpose of this RFA. As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project. The total project period for an application 
submitted in response to this RFA may not exceed 2 years. This RFA is a one-
time solicitation.  Competitive renewals of grants awarded under this RFA will 
not be accepted.  The earliest anticipated award date is September 30, 2002.

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.


NINDS intends to commit approximately $1.5 million in FY 2002 to fund 7 to 10 
new grants in response to this RFA. An applicant may request a project period 
of up to 2 years and a budget for direct costs of up to $125,000 per 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 NINDS provides 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.


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


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.   


Because the ultimate goal for assays developed under this RFA is HTS, 
investigators should describe their goals relevant to HTS. This should include 
a discussion of the goals and expected outcome of a chemical genetic screen or 
drug screen for which the assay is designed. In addition, the investigator 
should indicate their interest in having their assays adapted for screening at 
the NINDS HTS facility, or present a feasible alternative plan for using the 
assay in HTS.


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:

Direct your questions about scientific/research issues to:

Dr. Jill Heemskerk
Program Director, Technology Development
National Institute of Neurological Disorders and Stroke
NSC, Room 2229
6001 Executive Boulevard
Bethesda, MD  20892
Rockville, MD  20852 (For express or courier service)
Telephone:  (301) 496-5680
FAX:  (301) 480-1080

Direct your questions about peer review issues to:

Dr. Lillian Pubols
Chief, Scientific Review Branch, NINDS
Neuroscience Center, Suite 3208, MSC9529
6001 Executive Boulevard
Bethesda, MD  20892
Rockville, MD  20852 (For express or courier service)
Telephone: (301) 496-9223

Direct your questions about financial or grants management matters to:

Ms. Chris Davis
Grants Management Specialist
Grants Management Branch, DER, NINDS
Neuroscience Center, Room 3271
6001 Executive Boulevard
Bethesda, MD  20892
Rockville, MD  20852 (For express or courier service)
Telephone: (301) 496-7386
FAX:  (301) 402-0219

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 IC staff to estimate the potential review workload and plan 
the review.
The letter of intent is to be sent by February 26, 2002, to Dr. Jill Heemskerk 
at the address above. This letter may be sent by email. 


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive 
format. For further assistance contact GrantsInfo, Telephone 301/710-0267, 

Use the revised version of form PHS 398 with the following modifications:

o Research Plan:
The research plan may not exceed 15 pages. No appendices are permitted.

The instructions for this section suggest that the applicant state "the 
hypotheses to be tested." Hypothesis testing per se may not be the driving 
force in developing proposals for this RFA and, therefore, may not be 
applicable. Thus, the applicant should state the hypothesis, design and/or 
need which will drive the proposed research.

In this section it is important to clearly elaborate the rationale for the 
proposed assay and its intended purpose, e.g., drug screening or 
chemical genetics.

There is no requirement to generate preliminary data for these applications. 
However, the application should make clear that the proposed assay is 
scientifically sound, and any available preliminary data should be presented.

It is important to present long range plans for evaluating the significance of 
chemical leads resulting from future screening of the proposed assay. These 
may include descriptions of secondary in vitro screens and testing in 
animal models. 

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 includes 
step-by-step guidance for preparing modular grants.  Additional information on 
modular grants is available at

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:

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:

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:

Dr. Lillian Pubols
Chief, Scientific Review Branch, NINDS
Neuroscience Center, Suite 3208, MSC 9529
6001 Executive Boulevard
Bethesda, MD  20892
Rockville, MD  20852 (For Express or Courier Service)

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is received 
after that date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NINDS.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

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

o Receive a written critique 
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed, assigned a priority score
o Receive a second level review by the National Advisory Neurological 
Disorders and Stroke Council.


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:

o Significance
o Approach
o Innovation
o Investigator
o Environment
o Feasibility for HTS
o Future Plans

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 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 
methods? 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 support?

(6) FEASIBILITY FOR HTS: Although high throughput screening is outside the 
immediate scope of this announcement, is it feasible to adapt the assay to a 
high throughput format? Is it likely that the assay will produce reliable 
results in a high throughput screen? 

(7) FUTURE PLANS: For future use of the assay, has a facility been identified 
that can adapt and screen the assay in a high throughput format? Is there an 
adequate plan for evaluating the activities of compounds identified in a high 
throughput screen, e.g., in secondary screens? Are there important and well-
defined goals for the use of active compounds identified using this assay, 
either for drug discovery or for use as research tools?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, animals, 
or the environment, to the extent they may be adversely affected by the 
project proposed in the application.

o INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

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


Letter of Intent Receipt Date:    February 26, 2002
Application Receipt Date:         March 26, 2002
Peer Review Date:                 June/July 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002


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.


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 
a complete copy of the updated Guidelines are available at  
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.

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

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
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. 

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.

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

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of Federal 
Domestic Assistance No. 93.853, 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 
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.

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.