THE FUNCTION OF SYNAPTIC PROTEINS IN SYNAPSE LOSS AND NEURODEGENERATION

Release Date:  March 9, 2000

RFA:  NS-01-002

National Institute of Neurological Disorders and Stroke
 
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

In response to new research interest in the role of the synapse in the 
mechanisms of neurodegeneration, the National Institute of Neurological 
Disorders and Stroke (NINDS) invites qualified investigators to submit grant 
applications for focused studies of the synaptic function of hallmark 
proteins of neurodegenerative diseases to elucidate potential common 
mechanisms relevant to synapse loss and neurodegeneration. Although not 
formally participating in this request for applications, the National 
Institute on Aging is interested in research on the function of synaptic 
proteins in synapse loss and neurodegeneration in the aging nervous system.

RESEARCH OBJECTIVES

Background

Although there are likely to be varied etiologies among neurodegenerative 
diseases, one cellular commonality which exists among all neurons is the 
synapse. Synapses form the basic currency of information exchange between 
neurons, and as such, underlie the basic physiological function of circuits 
throughout the brain.  Degeneration of functional synapses is then of crucial 
importance to understanding the primary mechanisms of overall 
neurodegeneration.  While it is still unclear whether synapse loss precedes 
or follows neuron cell death, there is evidence to suggest the former: 
synapse loss has been observed to precede neuron loss in early Alzheimer’s 
Disease (AD). Several studies have correlated synapse loss with clinically 
defined neurological impairment.  For example, statistical analysis has shown 
that synapse loss is more closely correlated with cognitive impairment in AD 
than are plaques and tangles.  Moreover, a variety of proteins found in 
pathological hallmarks of neurodegenerative diseases are synaptic proteins or 
cleavage products of synaptic proteins.  These include APP, amyloid precursor 
protein, alpha-synuclein, the precursor of NAC peptide found in Lewy bodies 
in Parkinson’s Disease, and PrP, the prion protein - all found at the 
synapse. 

These observations emphasize that synapse loss is a central event in 
neurodegeneration and that certain synaptic proteins are involved in the 
neuropathology of disease.  Despite this fundamental understanding, there has 
been little systematic study of synapse loss or the role of synaptic proteins 
associated with pathology.  For example, the cleavage and biochemical 
processing of APP has been extensively studied in non-neuronal cells, but its 
processing during synaptic plasticity or synapse loss remains largely 
uninvestigated, and its normal function in the synapse is still unknown.

The overall purpose of this initiative is to support and stimulate focused 
studies of the synaptic function of the hallmark proteins of Parkinson’s and 
other neurodegenerative diseases to elucidate potential common mechanisms 
relevant to synaptic loss and neurodegeneration.
Although not formally participating in this request for applications, the 
National Institute on Aging is interested in research on the function of 
synaptic proteins in synapse loss and neurodegeneration in the aging nervous 
system.

The following investigations will be considered for this proposal:

O Cellular, molecular or animal studies on the function of synaptic 
proteins, such as APP, alpha-synuclein, or others implicated in 
neurodegenerative diseases, with main  emphasis on their synaptic function 
or their role in synaptic maintenance.

O Relationship of the function of particular synaptic proteins to synapse 
loss or neuronal loss; i.e. does dysfunction of synaptic proteins lead to 
synapse loss or neuron cell death? 

SPECIAL REQUIREMENT

Annual Meeting:  Synthesis of the component projects will require 
multidisciplinary communication of research results and opportunities. To 
facilitate such interactions, 
the NINDS will hold a yearly Workshop on Synaptic Roles in Neurodegeneration. 
The PI and 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 5 
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 total costs in FY 2001 
in to fund up to four 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 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 
provide support for this program, awards pursuant  to this RFA are contingent 
upon the availability of funds and receipt of a sufficient number of  
meritorious application. 
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 questions from potential applicants is welcome.

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

Diane D. Murphy, Ph.D.
Program Director
Neurodegeneration Program
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2202
6001 Executive Boulevard
Bethesda, MD 20892-9525
Telephone: 301/496-5680
FAX: 301/480-1080
E-mail: murphyd@ninds.nih.gov

Direct inquiries regarding fiscal matters to:

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

LETTER OF INTENT

Prospective applicants are asked to submit, by June 15, 2000 a Letter of 
Intent that includes a descriptive title and brief description of the 
proposed research, the name, address, telephone number, and email address 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 NINDS staff to estimate 
the potential review workload and plan the review.

The Letter of Intent is to be sent to:

Diane D. Murphy, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2202
6001 Executive Boulevard 
Bethesda, MD 20892-9525

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; from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
Room MSC 7910, Bethesda, MD 20892, telephone 301/435-0714; email: 
GrantsInfo@nih.gov.

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 title.  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

PHS 398

Budget Instructions

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, Suite 3208 MSC9529
6001 Executive Blvd.
Bethesda, MD 20892-9529
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 CSR and 
responsiveness by NINDS. Incomplete 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 (IC) 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 the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the (IC) National Advisory Council or Board.

REVIEW CRITERIA FOR RESEARCH GRANT APPLICATIONS: 

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.

(o  The adequacy of the proposed plan to share data, if appropriate.)

 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 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 have been 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 is scientific or ethical reasons not to include them. 
This 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 may also 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 RFA, "The function of 
synaptic proteins in synapse loss 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. Awards are made under authorization of the Public Health Service Act, 
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 
241 and 285) 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 American people.


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