Release Date:  March 27, 2000

RFA:  NS-01-006

National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  October 1, 2000
Application Receipt Date:       November 15, 2000



The National Institute of Neurological Disorders and Stroke (NINDS) is 
interested in promoting collaborations among junior investigators 
(Postdoctoral Fellows through Assistant Professors, or equivalent) to 
stimulate translational research in the field of epilepsy.  This 
exploratory grants program is being issued in conjunction with the 
White House-initiated, NIH-sponsored conference, "Curing Epilepsy:  
Focus on the Future."  To this end the NINDS invites 
exploratory/developmental research grant applications (R21) in patient-
oriented research, developmental neurobiology, genetics, advanced 
technology, imaging, pharmacotherapeutics, or other research areas, 
which are likely to lead to the cure of epilepsy (defined as "the 
prevention of epilepsy before it occurs in people at risk, and the 
cessation of seizures without therapy-associated side effects in those 
who develop the disease").  Emphasis will be placed on cross-
disciplinary collaborations, novel hypotheses, and unique approaches in 
applying fundamental neurobiological concepts to epilepsy research.  
Special consideration will be given to proposals that enhance the 
application of scientific knowledge to the understanding and treatment 
of the disorder.  This initiative requires collaborations of two or 
more junior investigators at different institutions, or in different 
laboratories within the same institution.  Investigators already 
working together at the same department are not eligible.


The purpose of this initiative is to 1) focus attention of young 
investigators on translational research in epilepsy; 2) promote the 
interaction of basic researchers and clinical scientists; and 3) 
provide preliminary information leading to the prevention and cure of 
epilepsy.  The ultimate goal is to effect meaningful advances in 
understanding the factors that contribute to epileptogenesis, and to 
develop interventions and effective treatments that improve the quality 
of life of people with the disorder.  


Epilepsy, characterized by the repeated occurrence of uncontrolled 
seizures, is one of the most common neurological disorders in our 
country.  It currently afflicts approximately 15 million Americans of 
all ages and backgrounds.  Epilepsy exacts an enormous toll on patients 
and their families, and has a huge impact on society related to loss of 
employment potential and the cost of medical care.  Despite many 
decades of research,  new anticonvulsant drugs, and advances in 
surgical therapy, a large number of people with epilepsy suffer from 
incompletely controlled seizures or the side effects of drugs or 
surgical treatment.  For these patients, current approaches to 
treatment will, at best, lessen but not prevent the occurrence of 
seizures. At worst, current therapies cause debilitating side effects 
and have little or no effect on seizures.  In addition, there has been 
complacency on the part of the medical establishment to accept partial 
control of seizures, or therapy-associated side effects, as an 
acceptable, long-term outcome for patients with epilepsy.   

Research in neuroscience has escalated rapidly in the past decade, 
especially in the areas of molecular biology, genetics, neuroimaging, 
and clinical diagnosis.  The purpose of this initiative is to apply 
this knowledge to curing epilepsy.  The initiative requires 
collaborations among two or more junior investigators at different 
institutions or at different laboratories within the same institution.  
The intent is to develop innovative proposals in translational epilepsy 
research.  Potential topic areas for proposals may include, but are not 
limited to: mechanisms for interrupting or modifying the process of 
epileptogenesis (i.e., approaches aimed at preventing the formation of 
a seizure focus in patients at risk for epilepsy); identification and 
characterization of genetic mutations that are the basis of inherited 
forms of epilepsy and which can provide a means of understanding the 
causes of seizures and determining treatment strategies; studies of the 
basic biology of neural development that might contribute to 
identification of the molecular basis for abnormalities observed in 
some patients; visualization of structural and functional changes in 
the brains of patients using advanced imaging technologies such as 
magnetic resonance spectroscopy, functional magnetic resonance imaging 
and magnetoencephalography; development of new classes of 
pharmacological agents and other effective therapeutic strategies such 
as focal brain stimulation and brain irradiation; and, innovative 
clinical trial methodologies to quickly identify effective 
antiepileptogenic interventions.  A brief description of the areas of 
emphasis follows:

Interrupting epileptogenesis -- Epilepsy may develop after common brain 
"insults" including stroke, trauma, prolonged febrile convulsions, 
meningitis and encephalitis, or in the course of chronic 
neurodegenerative diseases such as Alzheimer's disease.  Being able to 
identify whether the epilepsy develops when the lesion first occurs, or 
later when the first seizure appears, will have a major impact on the 
ability to prevent, or "cure", epilepsy.  Animal models of brain injury 
have shown the progression of anatomic, physiologic and molecular 
changes that occur; however, there has been little success in 
preventing the development of epilepsy after injury in these models.  
Treatment with antiepileptic drugs has failed to prevent epilepsy in 
patients after head trauma in controlled clinical trials.  Grant 
applications are encouraged that address topics such as brain 
development, cell loss, neurogenesis, cell migration, axonal or 
dendritic reorganization, seizure- or injury-induced changes in gene 
expression, modulation of receptor functions, and other mechanisms that 
may contribute to altered network function in the CNS.  The 
applications should address how this knowledge can be applied to the 
formation of better hypotheses about mechanisms of epileptogenesis and 
better models to test new approaches to prevention.  

Monitoring epileptogenesis -- Structural brain imaging has been used to 
identify epileptogenic lesions in patients with seizures and has 
revolutionized our understanding of the basic mechanisms of epilepsy.  
The ability to monitor the process of epileptogenesis is an essential 
component of any approach aimed at preventing epilepsy or treating 
individuals known to be at high risk for developing epilepsy.  Studies 
are encouraged that address the monitoring of changes in lesions (e.g., 
tumor growth), anatomy (mesial temporal sclerosis),  and electrical 
activity.  Studies that characterize receptors and explain biochemical 
changes may be able to provide insights into focal and regional 
pathology that lead to predicting responsiveness to antiepileptic 
medications.  An emerging area of research involves the concept of 
network synchrony.  Neuronal network synchrony increases prior to a 
seizure and remains elevated for hours following the event.  The 
ability to assess these dynamic changes and apply measurements of 
neuronal network synchrony to interictal periods and ictal events may 
help predict, and prevent, seizure occurrence.

Genetic strategies -- The epilepsies are a heterogeneous group of 
disorders with many underlying causes.  Recent advances in molecular 
biology have provided insight into the genetic basis of inherited 
epilepsies in humans and in model organisms such as the mouse.  
Epilepsy genes have been found to fall into several distinct 
categories.  Mutations have been identified in genes that encode 
voltage-gated or ligand-gated ion channels associated with human 
idiopathic epilepsies.  They are predicted to directly or indirectly 
increase neuronal excitability, which lead to seizures.  Mouse mutants, 
including phenotypes with generalized spike-wave discharges, also 
provide evidence of epilepsy as an ion channel disease.  Mutations in a 
gene encoding an actin-binding protein that initiates neuronal 
migration, and two genes that encode possible cell signaling proteins 
that direct neuronal migration, have been identified in neuronal 
migration disorders.  Other genes involve progressive neurodegeneration 
and disturbances of cerebral energy metabolism.  The exact function of 
these various genes, and the pathways of which they are a part, remain 
to be discovered.  However, it is expected that further discoveries of 
genes associated with epilepsy, as well as studies of the mechanisms by 
which genes cause epilepsy, will substantially advance our 
understanding of the biological basis of many forms of seizure 
disorders.  This will, in turn, lead to progress in the treatment and 
cure of patients with epilepsy.

Therapeutic strategies -- The goal of curing epilepsy is to identify 
individuals who are at risk for developing the disorder and to provide 
effective treatment without therapeutic side effects to those who have 
the disease.  Topics to address may include, but are not limited to:  
the effectiveness of early pharmacologic interventions in patients 
presenting with seizures; whether medications may exacerbate long-term 
problems such as seizure severity and associated cognitive problems; 
studies to better analyze changes in the CNS of high-risk individuals; 
evaluation of surgical approaches, including early intervention; 
alternative therapies such as gene therapy or cell therapy; surrogate 
markers that can be used to monitor new therapies; and, new designs for 
intervention studies.  Exploratory research studies in this area will 
hopefully provide the necessary information for determining effective 
preventative strategies and rational therapeutic designs.

Scope and objectives

Applications submitted in response to this RFA may address any of the 
above areas of emphasis.  Examples of approaches responsive to this RFA 

o  Adaptation of models of neuronal development, injury or degeneration 
to the study of epilepsy and epileptogenesis.

o  Novel strategies and hypotheses that enhance understanding of the 
mechanisms of pathogenesis.

o  Proposals to identify genes involved in the epilepsies.

o  Studies directed at the development of therapeutic regimens.  This 
could include identification of appropriate clinical markers 
(neuroimaging, neurophysiologic, neurochemical), or preliminary 
information for developing clinical protocols, methodologies, and/or 
pharmacological agents.

o  Development of new technologies relevant to the areas of emphasis in 
this initiative.


The research plan should include a section entitled, "Role of 
Collaborators" (not to exceed three pages) that discusses the 
contribution of each of the collaborators to the overall effort and how 
the different parts of the project interact to achieve the proposed 
goals.  The Research Plan must be soundly developed with well-defined 
and clear objectives.  The Approach should make use of appropriate 
concepts and methodologies.  Applicants should elaborate on innovative 
aspects of the proposed research, novel collaborations, and special 
attributes of the resources and environment.  In addition, applicants 
must identify how the exploratory studies could result in new insights 
or capabilities for translational research in epilepsy.


This RFA will use the National Institutes of Health (NIH) 
exploratory/developmental  research grant award mechanism (R21).  The 
R21 awards are used for support of creative, novel, and/or high 
risk/high payoff approaches that could produce innovative advances in 
this field.  This includes feasibility studies, protocol planning, and 
the incorporation of new disciplines and technologies.  This mechanism 
provides the means to acquire the necessary pilot information, to 
attract talented new investigators from related disciplines, and to 
foster the development of interdisciplinary, inter-institutional 
collaborative efforts among investigators with diverse training and 
expertise.  Responsibility for the planning, direction, and execution 
of the proposed project will be solely that of the applicant.  This RFA 
is a one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications 
and be reviewed according to the customary peer review procedures.  The 
earliest anticipated award date is July 1, 2001.

Specific application instructions have been modified to reflect 
“MODULAR GRANT” and “JUST-IN-TIME” streamlining efforts being examined 
by the NIH.  Complete and detailed instructions and information on 
Modular Grant applications can be found at


NINDS intends to commit up to $1 million total costs, in FY 2001, to 
fund new research grants in response to this RFA.  An applicant may 
request a project period of up to three years and a budget for direct 
costs of up to $150,000 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 
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. 


Applications may be submitted by foreign or domestic, for-profit and 
nonprofit organizations, public and private, such as universities, 
colleges, hospitals, laboratories, units of State and local 
governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.


Inquiries concerning this RFA are encouraged. The opportunity to 
clarify any issues or questions from the potential applicants is 

Direct inquiries regarding programmatic issues to:

Margaret P. Jacobs
Program Director, Epilepsy Research
National Institute of Neurological Disorders
  and Stroke, NIH
Neuroscience Center, Room 2110-
6001 Executive Boulevard
Bethesda, MD 20892-9523
Phone:   301/496-1917
Fax:      301/480-2424

Direct inquiries regarding fiscal matters to:

Jerome Lofton
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3248
Bethesda, MD  20892-9537
Telephone:  (301) 496-9231
FAX:  (301) 402-0219


Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed research, the names, 
addresses and telephone numbers of the collaborating investigators, the 
identities of other key personnel, and the number and title of the RFA 
in response to which the application may be submitted.  Although a 
letter of intent is not required, is not binding, and does not enter 
into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and 
avoid conflict of interest in the review.

The letter of intent is to be sent by October 1, 2000, (fax and e-mail 
encouraged) to:

Margaret P. Jacobs
Program Director, Epilepsy Research
National Institute of Neurological Disorders
  and Stroke, NIH
Neuroscience Center, Room 2110
6001 Executive Boulevard
Bethesda, MD 20892-9523
Phone:   301/496-1917
Fax:      301/480-2424
Rockville, MD 20852 (for express/courier service)


Letter of Intent Receipt Date:  October 1, 2000
Application Receipt Date:  November 15, 2000
Peer Review Date:  March 2001
Council Review:  May 2001
Earliest Anticipated Start Date:  July 1, 2001


The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants.  These forms are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910,Bethesda, MD 20892-7910, 
telephone 301/710-0267, email: 

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
Failure to use this label could result in delayed processing of the 
application such that it may not reach the review committee in time for 
review.  In addition, the RFA title and number must be typed on line 2 
of the face page of the application form and the YES box must be 

The sample RFA label available at: has been 
modified to allow for this change.  Please note this is in pdf format.


The modular grant concept establishes specific modules in which direct 
costs may be requested as well as a maximum level for requested 
budgets.  Only limited budgetary information is required under this 
approach.  The just-in-time concept allows applicants to submit certain 
information only when there is a possibility for an award.  It is 
anticipated that these changes will reduce the administrative burden 
for the applicants, reviewers and Institute staff.  The research grant 
application form PHS 398 (rev. 4/98) is to be used in applying for 
these grants, with the modifications noted below.

Budget Instructions

Modular grant applications in response to this RFA will request direct 
costs in $25,000 modules, up to a total direct cost of $150,000 per 
year for up to three years.  The total direct costs must be requested 
in accordance with the program guidelines and the modifications made to 
the standard PHS 398 application instructions described below:

PHS 398

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $150,000 per year) and 
Total Costs [Modular Total Direct plus Facilities and Administrative 
(F&A) Costs] for the initial budget period.  Items 8a and 8b should be 
completed indicating the Direct and Total Costs for the entire proposed 
period of support, which is not to exceed 3 years.

Page 4 of the PHS 398.  It is not required and will not be accepted 
with the application. 

the categorical budget table on Form Page 5 of the PHS 398.  It is not 
required and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget 
Narrative page. (See for sample 
pages.)  At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o  Under Personnel, list key project personnel, including their names, 
percent of effort, and roles on the project.  No individual salary 
information should be provided.  However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request. 

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000.  List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of key personnel, and the role on the project.  Indicate whether 
the collaborating institution is foreign or domestic.  The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount.  Include the Letter of Intent to 
establish a consortium.

Provide an additional narrative budget justification of any variation 
in the number of modules requested.

o  BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's qualifications 
for a specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team.  A biographical sketch is 
required for all key personnel, following the instructions below.  No 
more than three pages may be used for each person.  A sample 
biographical sketch may be viewed at: 

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  RESEARCH PLAN:  Applications in response to this RFA should include 
an Introduction, not to exceed 3 pages, as explained above under 
Research Objectives.  This is not included as part of the 25 page 

o  CHECKLIST:  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate 
the type of agreement and the date.  All appropriate exclusions must be 
applied in the calculation of the F&A costs for the initial budget 
period and all future budget years.

o  The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.

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 time of submission, two additional copies of the application must be 
sent to:

Dr. Lillian Pubols
Chief, Scientific Review Branch
Division of Extramural Activities, NINDS
Neuroscience Center, Room 3208
6001 Executive Blvd.
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that 
date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed. 


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 

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

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments reviewers will be asked to discuss the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals.  Each of these criteria will be addressed and 
considered in assigning the overall score, weighting them as 
appropriate for each application.  Note that the application does not 
need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
an investigator may propose to carry important work that by its nature 
is not innovative but is essential to move a field forward.

Given that the purpose of this R21 initiative is to encourage 
collaborations in translational research in epilepsy, the focus of 
review will be on innovation in the development of novel concepts, new 
methodologies, and cross-collaborations.  Since the developmental 
research projects proposed under this RFA may contain preliminary tests 
of feasibility, substantial risks, and challenges to current concepts, 
and may lack the amount of preliminary data and background experience 
normally found in an R01 application, reviewers will weigh the 
following review criteria accordingly:  

(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?  In the context of the R21 
mechanism, a strong rationale and conceptual framework are normally 
sufficient for establishing the feasibility of the project, in lieu of 
preliminary data.

(3) Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?  If the project is not innovative but is essential to 
move the field forward, the applicant should mention and discuss this 
aspect in the proposal.

(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?

(5) Environment:  Does the scientific environment in which the work 
will be done contribute to the probability of success?  Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements?  Is there 
evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will 
also be evaluated.

o  The reasonableness of the proposed budget and duration in relation 
to the proposed research.

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


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.


It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994  (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, 
Number 11, March 18, 1994, and are available on the web at:


It is the policy of the NIH that children (i.e., individuals under the age of 
21) must be included in all human subjects' research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them.  This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998 and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010", a PHS-
led national activity for setting priority areas.  This Request for 
Application (RFA), “Innovations in Translational Epilepsy Research,” is 
related to the priority area of chronic disabling conditions.  Potential 
applicants may obtain a copy of Healthy People 2010 at


This program is described in the Catalog of Federal Domestic Assistance 
No.93.853.  Awards are made Federal Domestic Assistance No.  Awards are made 
under authorization of Sections 301 and 405 of the of the Public Health 
Service Act as amended (42 USC 241 and 284) and administered under NIH grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking 
in certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the America.

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