Release Date:  June 20, 2001

PA NUMBER:  PAR-01-111 (This PA has been modified, see PA-05-095)

National Institute of Neurological Disorders and Stroke



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.  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 junior 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 

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 PA may address any of the above areas of 
emphasis.  Examples of approaches responsive to this PA include:

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.


This PA 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. 

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 


An applicant may request a project period of up to two years and a budget for 
direct costs of up to $150,000 per year. Indirect costs associated with any 
contractual/consortium arrangement should be incorporated into the direct cost   
calculation of the project.  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 PA 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 PA are encouraged. The opportunity to clarify any issues 
or questions from the potential applicants is welcomed.

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
Email:   mj22o@nih.gov

Direct inquiries regarding fiscal matters to:

Ken Bond
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3290
Bethesda, MD  20892-9537
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:   kb33s@nih.gov


The research grant application form PHS 398 is to be used in applying for these 
grants, and will be accepted at the standard application deadlines as indicated in 
the application kit.  Application kits are available at most institutional offices 
of sponsored research and may be obtained 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. 


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 is to be used in applying for these grants, with the modifications 
noted below.

Budget Instructions

Modular grant applications in response to this PA will request direct costs in 
$25,000 modules, up to a direct cost of $150,000 per year for up to two years. Both 
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 2 years.

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

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 https://grants.nih.gov/grants/funding/modular/modular.htm 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 all 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 

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 all 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 

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 PA should follow the 
instructions for NINDS R21 grant applications 
http://www.ninds.nih.gov/funding/r21guidelines.htm The research plan, not 
including the Introduction (for resubmissions only), is limited to 15 pages. No 
appendix is allowed


The research plan should include a section entitled “Role of Collaborators,” 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.

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

Lillian M. Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center Suite #3208
6001 Executive Blvd.
Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852)
Tel.: 301-496-9223
Fax: 301-402-0182
e-mail: LP28E@NIH.GOV

The Center for Scientific Review (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 substantial revisions of applications already 
reviewed, but such applications must include an introduction addressing the 
previous critique. 

Applications that are complete and responsive to the PA 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.  

Given that the purpose of this R21 initiative is to encourage collaborations 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 PA 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 methods?  
Are the aims original and innovative? Does the project challenge existing paradigms 
or develop new methodologies or technologies?  

(4) Investigators:  Are the investigators appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level of 
the principal investigators 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 


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 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 
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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 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 RFA (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.


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 Program Announcement “Innovations in 
Translational Epilepsy Research For Junior Investigators” is related to the 
priority area of chronic disabling conditions.  Potential applicants may obtain a 
copy of Healthy People 2010 at http://www.health.gov/healthypeople.


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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
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Bethesda, Maryland 20892
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and Human Services (HHS)
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