MITOCHONDRIAL FUNCTION AND NEURODEGENERATION

Release Date:  March 9, 2000

RFA:  NS-01-003

National Institute of Neurological Disorders and Stroke
National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  June 15, 2000
Application Receipt Date:       August 17, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

To stimulate increased research interest in the role of mitochondria in the 
mechanisms of neurodegeneration, the National Institute of Neurological 
Disorders and Stroke (NINDS) and the National Institute of Environmental 
Health Sciences (NIEHS) invite qualified investigators to submit grant 
applications for focused studies of mitochondria-mediated effects on the 
function of living neurons that may be important in the development of 
disease.

Neurodegenerative disorders result in the progressive deterioration of 
function in the central nervous system (CNS). Parkinson’s Disease (PD), 
Huntington’s disease (HD), Alzheimer’s disease (AD) and Amyotropic lateral 
sclerosis (ALS) all affect different cell types within the CNS, but there are 
striking similarities in the progression of disease within these cells. There 
are mutations in known genes associated with each of these diseases. However, 
their identification has left some hallmarks of neurodegeneration unexplained. 
One feature that these diseases share is the onset of symptoms late in life. 
The identification of linked mutations raises the paradox that, while the 
mutated proteins are present throughout life, symptoms only appear in mid-life 
or later.  A second common theme suggested by these mutations is that, 
although these genes are expressed in all cells, degeneration is limited to 
restricted regions of the CNS. Because the mitochondrial composition in a cell 
can vary with time and cell-type, both late onset and cell specificity may be 
explained by the involvement of mitochondrial dysfunction.

There are hints that mitochondrial dysfunction underlies many forms of 
neurodegeneration. Mitochondrial DNA from Alzheimer’s and Parkinson’s patients 
has been shown to contain deletion mutations,  and mitochondrial activity is 
altered in some ALS patients. Furthermore, compounds that affect mitochondrial 
function can mimic neurodegenerative disease symptoms in animal models: MPTP, 
a mitochondria-specific toxin, can result in Parkinson’s disease, and 
inhibition of complex II activity by 3NP can produce HD-like symptoms. 
Suggestions of mitochondrial involvement pervade the study of 
neurodegenerative disease in general. Thus, it is important to explore the 
possibility that mitochondrial dysfunction may be a significant factor in the 
late onset and progression of neurodegenerative disease.

The purpose of this Request for Applications (RFA) is to explore the 
possibility of a link between mitochondrial dysfunction and the onset of 
neurodegenerative disease. The role of mitochondria in apoptosis is not 
encouraged in this initiative, in part because this is already being 
intensively investigated. 

RESEARCH OBJECTIVES

The overall purpose of this initiative is to support and stimulate focused 
studies of mitochondria-mediated effects on the function of living neurons 
that may be important in the development of disease. Some example areas of 
interest are described below:

1. Mitochondrial genetics and neurodegenerative disease.
Because cells carry a mix of mitochondrial genotypes, mitochondrial defects 
can be masked by the presence of functional mitochondria. Over the course of a 
lifetime, the ratio of mitochondrial types within a cell or tissue can change. 
This unusual aspect of mitochondrial genetics could account for the late onset 
of neurodegenerative disease. This could also explain why neurodegenerative 
diseases often have complicated genetic profiles: variability in the presence 
of a disease in family members with shared risk factors and even sporadic 
occurrence could be accounted for by variability in the prevalence of defects 
carried by mitochondria. Further, it appears that the distribution of 
mitochondrial mutations can vary among cell types, possibly providing a 
partial explanation for cell-type specificity in neurodegeneration. New 
genetic investigations are requested into the role of inherited or acquired 
mitochondrial mutations in the late onset or cell specificity of 
neurodegeneration.

2. Uncoupling proteins as therapeutic targets in the treatment of 
neurodegenerative disease. The recent discovery that mitochondrial uncoupling 
proteins are broadly expressed suggests a mechanism for the manipulation of 
mitochondrial activity. By modulating the activity of uncoupling proteins, it 
may be possible to regulate the metabolic output of mitochondria. If 
mitochondrial dysfunction lies at the root of neurodegenerative disease, the 
application of such a strategy may slow or stop progression of these diseases.

SPECIAL REQUIREMENTS

Annual Meeting: Progress in understanding the role of mitochondria in 
neurodegenerative disease will be facilitated by multidisciplinary 
collaboration and communication of research results and opportunities. To 
promote such interactions, the NINDS and NIEHS will hold a yearly meeting. The 
PI and at least one other representative from each project will attend this 
meeting in Rockville, Maryland. This meeting will also be open to interested 
members of the research community. The cost of participating in the annual 
meeting should be built into the proposed budget.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) R01 award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
application submitted in response to this RFA may not exceed five years.  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 anticipated 
award date is April 1, 2001.

FUNDS AVAILABLE 

The NINDS intends to commit approximately $1 million and NIEHS $250,000 in FY 
2001 to fund up to five new and/or competitive continuation grants in response 
to this RFA. An applicant may request a project period of up to five years and 
a budget for direct costs of up to $250,000 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 and NIEHS 
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.  Although not formally participating in this RFA, 
the National Institute on Aging is interested in research on the role of 
mitochondria in neurodegenerative diseases of the aging nervous system.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit 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

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

Direct inquiries regarding scientific and other application-related issues to:

Jill E. Heemskerk, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2204
6001 Executive Boulevard 
Bethesda, MD 20892-9525 (for courier service, use: Rockville, MD  20852)
Telephone: (301) 496-5680
FAX: (301) 480-1080
E-mail: jill_heemskerk@nih.gov

Annette G. Kirshner, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-23
Research Triangle Park, NC 27709
Telephone: (919) 541-0488
FAX: (919) 541-5064
E-mail: kirshner@niehs.nih.gov

Direct inquiries regarding review issues to:

Dr. Lillian Pubols
Chief, Scientific Review Branch, NINDS, NIH
Neuroscience Center, Room 3208
6001 Executive Boulevard 
Bethesda, MD 20892-9525 (US Mail)
Rockville, MD 20852 (for express/courier service)

Direct inquiries regarding fiscal matters to:

Kimberly Pendleton
Grants Management Specialist
Grants Management Branch, DER
Neuroscience Center, Room 3254
6001 Executive Boulevard 
Bethesda, MD 20892-9525
Telephone: (301) 496-9231
FAX: 301-402-0219
EMAIL: kp33e@nih.gov

Dorothy G. Duke
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-22
Research Triangle Park, NC 27709
Telephone: (919) 541-2749
FAX: (919) 541-2860
Email: mineo@niehs.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, 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 plan the review.

The letter of intent is to be sent to the address below by June 15, 2000.

Jill E. Heemskerk, Ph.D.
Program Director
Neurodegeneration Program
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2204 
6001 Executive Boulevard 
Bethesda, MD 20892-9525
(for courier service, use: Rockville, MD  20852)

SCHEDULE SUMMARY

Letter of Intent Receipt Date: June 15, 2000
Application Receipt Date: August 17, 2000
Peer Review Date: November 2000
Council Review: February 15-16, 2001
Earliest Anticipated Start Date: April 1, 2001

APPLICATION PROCEDURES

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 301/435-0714, email: 
GrantsInfo@nih.gov.

The RFA label available in the PHS (rev. 4/98) 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 sample RFA label available 
at:http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified 
to allow for this change.  Please note this is in pdf format.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 

Budget Instructions

PHS 398

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year.  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:

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) 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.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 
4 of the PHS 398. It is not required and will not be accepted with the
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 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 http://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 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 for 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: 
http://grants.nih.gov/grants/funding/modular/modular.htm

- 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 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:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Dr. Lillian Pubols
Chief, Scientific Review Branch, NINDS, NIH
Neuroscience Center, Room 3208
6001 Executive Boulevard 
Bethesda, MD 20892-9525 (US Mail)
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. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NINDS and NIEHS.  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. Applications 
that are relevant to NIEHS will be assigned to them after review. 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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Advisory Councils or Boards of NINDS and NIEHS.

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 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 method? 
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?

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

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.


INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 are 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, Vol. 23, No. 
11, March 18, 1994, and is available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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 the 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: http://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.

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.  Reviewers are cautioned 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 Request for Applications (RFA), 
Mitochondrial Function and Neurodegeneration, 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 No. 
93.853 and 93.113.  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 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 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 
American people.

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