THE ROLE OF PARKIN AND RELATED PROTEINS IN PARKINSON’s DISEASE

Release Date:  April 24, 2000

RFA:  NS-01-005 

National Institute of Neurological Disorders and Stroke
 
Letter of Intent Receipt Date:  July 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 discoveries on parkin in the neurodegeneration of 
Parkinson’s Disease, the National Institute of Neurological Disorders and 
Stroke (NINDS) invites qualified investigators to submit grant applications 
for focused studies of the role of parkin and related proteins in Parkinson’s 
disease and other neurodegenerative disorders. 

The overall purpose of this initiative is to support and stimulate focused 
studies of the role of parkin and related proteins in Parkinson’s and other 
neurodegenerative diseases to elucidate potential common mechanisms relevant 
to neurodegeneration.

RESEARCH OBJECTIVES

Background

Parkinson's Disease (PD) is the second most common neurodegenerative disease 
after Alzheimer's Disease. While Parkinson's symptoms usually appear in the 
late 40's or 50's, they may manifest as early as the late 20's.  Recently, a 
familial early onset form has been described as Autosomal Recessive Juvenile 
Parkinsonism (AR-JP), and has been linked to a gene which codes for a protein 
called parkin. Mutations in the parkin gene have been found in a Japanese 
family, and also in a Greek family, and it is expected that additional 
families will demonstrate mutations once more patients have been screened. 
Like the alpha-synuclein protein, also genetically mutated in Parkinson's 
Disease, the cellular functions of parkin are unknown.  However, unlike 
synuclein, the structure of the parkin protein gives significant clues to its 
possible function, including potential roles in the ubiquitin pathway and in 
gene transcription.

The amino terminus of parkin bears sequence homology to ubiquitin, suggesting 
it may attach to proteins and thereby target them for a variety of cellular 
destinations, including endosomes, lysosomes, or autophagic vesicles. 
Additionally, there is a RING finger motif at the carboxy terminal end. 
Recently, RING-finger motifs have been shown to mediate a step in 
ubiquitination of proteins destined for degradation by the proteasome in 
cells, and at least one mutation in parkin (T240-R) is found at the start of 
the RING finger sequence. Thus, parkin may function as an intermediate in the 
ubiquitin pathway, controlling levels of other proteins or itself by 
regulated degradation. In addition to the parkin mutations in AJ-RP, a 
polymorphism in the ubiquitin carboxy-terminal hydrolase gene (UHC-L1) has 
been discovered in a very few individuals with PD. It comprises 1-2% of total 
soluble brain protein and is hypothesized to hydrolyse polymeric ubiquitin to 
monomeric ubiquitin (deubiquitination, or DUB enzyme). UHC-L1, along with 
ubiquitin, is found in Lewy bodies. So while the frequency of UHC-L1 
mutations are probably very low, it further implicates disturbances in the 
ubiquitin pathway as potentially pathogenic in different forms of PD.

Parkin homologs containing ubiquitin-like sequences and accompanying RING 
fingers have been identified in a variety of systems, including mouse, 
Drosophila, C. elegans, and yeast. The RING finger domain in the mouse 
homolog of parkin (RBCK1) functions as a transcriptional activator, and 
transcription is abolished when the RING domain is mutated. These studies 
suggest that the parkin RING finger may directly regulate gene expression. 
The ubiquitin-like sequence also implicates parkin in genetic transcription - 
similar to targeting proteins to lysosomes, the ubiquitin sequence may target 
transcriptional proteins to the nucleus.

Although not formally participating in this request for applications, the 
National Institute of Environmental Health Sciences (NIEHS) is interested in 
research related environmental factors which affect parkin and will consider 
funding applications which are in the direct mission of their institute.

Although not formally participating in this request for applications, the 
National Institute on Aging (NIA) maintains a strong interest in supporting 
studies on the role of mutated proteins in Parkinson’s disease and other 
neurodegenerative disorders. 

The following investigations will be considered for this proposal:

O More expansive genetic studies on the parkin and UHC-L1 mutations in PD 
families, including those not yet screened for these mutations.

O Creation of parkin models in various animal systems, including mice, 
flies, etc. to better understand parkin function, including the study of 
cellular interactions of parkin with other proteins.

O Structure/function studies of the RING finger domain in parkin or related 
PD proteins, including their possible role in ubiquitination.

O Role of parkin or related PD proteins as potential transcriptional 
activators. 

MECHANISM OF SUPPORT

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 
http://grants.nih.gov/grants/funding/modular/modular.htm

This RFA will use the National Institutes of Health (NIH) regular research 
grant award mechanism (R01).  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 (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 earliest anticipated award date is 
April 1, 2001.

FUNDS AVAILABLE

The NINDS intends to commit up to $1 million in total costs to fund up to 
four successful applications in FY 2001 in response to this RFA. Applicants 
may request up to five years of support. In all cases, Facilities and 
Administrative (indirect) costs will be awarded based on the negotiated 
rates. 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. 

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

Direct inquiries regarding review issues 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)
Telephone:  301/496-9223
Email: pubolsl@ninds.nih.gov

Direct inquiries regarding fiscal matters to:

Kimberly Pendleton
Grants Management Specialist
Grants Management Branch, DER, NINDS
Neuroscience Center
6001 Executive Blvd., Room 3254
Bethesda, MD 20892-9537
Telephone: (301) 496-9231
FAX: 301-402-0219
EMAIL: kp33e@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit, by July 15, 2000 a Letter of 
Intent that includes a descriptive title, 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 
Institute staff to estimate the potential review workload and avoid conflict 
of interest in 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
6001 Executive Blvd., Room 2202
Rockville, MD 20852
FAX: 301/480-1080
E-mail: murphyd@ninds.nih.gov

SCHEDULE SUMMARY

Letter of Intent Receipt Date:  July 15, 2000
Application Receipt Date:       August 17, 2000
Peer Review Date:               December 2000
Council Review:                 February 2001
Early 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, Room MSC 7910, Bethesda, MD 20892, telephone 301/710-0267; 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.  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.

There is a sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Note this is in 
pdf format.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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 will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.)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 $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 (3) 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 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 the 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 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 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.

NIH POLICY AND GUIDELINES ON THE 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), "The Role of Parkin and Related Proteins in Parkinson's 
Disease" is related to the priority area of Neurodegenerative Diseases.  
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 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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