THE ROLE OF THE ENVIRONMENT IN PARKINSON'S DISEASE

Release Date:  September 21, 1999

RFA:  ES-00-002

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

Letter of Intent Receipt Date: November 5, 1999
Application Receipt Date: January 11, 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 THAT 
ARE RESPONDING TO THIS RFA.

PURPOSE

The objective of this Request for Applications (RFA) is to stimulate research
on the relative roles of environmental, endogenous neurochemical and modifying
genetic factors in the cause of Parkinson's disease.   Recent evidence from
twin studies has shown that genetics plays less of a role and environmental
factors a potentially greater role than previously thought in the development
of late-onset Parkinson's disease (PD).  In response to this finding, the
National Institute of Environmental Health Sciences (NIEHS) and National
Institute of Neurological Disorders and Stroke (NINDS) invites scientists to
submit research grant applications for research aimed at elucidating the role
of the environment in the development of Parkinson's disease.  The results of
these investigations will contribute to clarifying the part environmental 
factors play in the etiology of this disease.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas. This RFA, "The Role of the Environment in
Parkinson's Disease," is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000

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.

FUNDS AVAILABLE

The total estimated funds available for support of the research project grant
(R01, R21) award mechanisms in this Request for Applications are $4,000,000
per year.  This level of expenditure is contingent upon the receipt of a
sufficient number of applications directly relevant to the objectives of this
RFA that are of high scientific quality as judged by a peer-review merit 
evaluation and the actual available funds. 

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project
grant (R01, R21) award mechanisms.  The R01 grant mechanism supports a
discrete, specified, circumscribed research project that is well-grounded on
current knowledge and to be performed by the named investigator(s) in an area
of research representing his/her/their specific interest and competencies. 
The R21 is an exploratory/developmental grant mechanism that supports the
development of new research activities in categorical program areas with more
restricted levels of time and funding.    

For R21s, a maximum of $100,000 (four $25,000 modules) per year for a maximum
of two years will be allowed.  For R01s, applications requesting up to
$250,000 direct cost must be submitted in the modular grant format.  R01
applications requesting budgets greater than $250,000 must submit detailed
budget information with the application. 

The total project period for an application submitted in response to this RFA
may not exceed two years for an R21 or five years for an R01.  Responsibility
for the planning, direction, and execution of the proposed project will be
solely that of the applicant.

For administrative reasons, the primary assignment of all applications will
initially be to the NIEHS.  After discussion with the other participating
Institute programs, applications may be reassigned where they are
programmatically most appropriate. 
 
Background

While much of the previous research in Parkinson's disease (PD) has focused on
the underlying biological processes critical to disease manifestation in the
hopes of developing new treatments, the relative roles of environmental,
endogenous neurochemical and modifying genetic factors in the causation of
neurodegenerative diseases remain unclear.  For example, it is not clear
whether differences in prevalence rates of PD in various communities are due
to the differential distribution of a hypothetical environmental toxicant or
are more frequent where a heritable defect is more common.  Moreover, analytic
epidemiological studies have varied in case and control selection methodology
and venues (e.g., clinics, population bases, different countries) 
partly accounting for the disparate conclusions reached by investigators. 

New evidence from a recent study showed that there was no statistically
significant difference in the incidence of late-onset (over the age of 50) PD
between monozygotic and dizygotic twins.  
This finding indicates a potentially greater role for environmental agents in
the etiology of the disease than previously appreciated.  However, the
relative roles of genetic susceptibility and environmental factors in
triggering PD remain to be determined.  The observation that cigarette 
smoking appears to protect against the development of PD illustrates the
complex role that exogenous agents play in the development of PD.  

Other epidemiological studies have implicated pesticide exposure and rural
living as risk factors for developing PD.  New evidence has emerged from one
study showing that long-term occupational exposure to certain combinations of
metals is significantly associated with developing PD.  This is the first
study to link a 20- year or more occupational exposure to heavy metals with a
chronic neurodegenerative disorder.  The study also found a link to PD and 
occupational exposure to herbicides, insecticides and farming.  

Findings from research using animal models and in vitro techniques have begun
to support some of these epidemiological findings.  For example, a study in
mice investigating the role of organochlorine pesticides in altering normal
dopaminergic function has led to the observation that the pesticide,
heptachlor significantly inhibits vesicular uptake of dopamine making the 
striatal neurons more vulnerable to degeneration.

RESEARCH OBJECTIVES

The National Institute of Environmental Health Sciences convened a Concept
Forum on the Role of the Environment in Parkinson's Disease on July 22, 1999
to evaluate the current evidence and identify future research needs in three
areas:  basic research, epidemiological research, and clinical research.  The
Forum concluded that elucidating the role of the environment in the etiology
of PD is important in developing a better understanding of the disease process
for both its prevention and treatment.

Therefore, applications are solicited in, but not limited to, the following
areas:

-  Research aimed at understanding the mechanism by which environmental
exposure, endogenous susceptibility factors, and increasing age contribute to
the etiopathology of PD.  Of particular significance may be those approaches
that can be used across species from lower animals to humans.  Such approaches
permit a precise characterization in animal models of alterations arising from
defined environmental exposures which can serve as a cogent guide to
underlying cellular and molecular mechanisms necessary to support
epidemiological studies.

-  Epidemiological studies targeted to specific environmental agents and/or
combination of factors associated with an increased risk for neurodegenerative
disorders.  These studies may target populations already characterized in
terms of the incidence and risks for neurodegenerative diseases (e.g., farmers
with significant exposure to pesticides) and should use advanced techniques in
exposure assessment as well as biomarkers of exposure and effect when
possible.

-  Development of biomarkers of preclinical disease to identify those at risk
for selected environmental toxicants, and to identify those who would benefit
from trials of possibly neuroprotective drugs.

-  Studies focusing on early disease which help clarify the contributions and
attributable risks from environmental or gene/environmental interactions. 

-  Studies developing models of neurodegenerative disease from low-level
and/or chronic exposure to environmental agents and synergistic chemical
interactions leading to neuronal injury.  

-  Development of genetically modified transgenics or knockout animals to
study increased susceptibility to environmentally induced neurodegeneration
and the efficacy of therapeutic interventions.

-  Elucidation of gene-environment interactions using molecular epidemiology
tools. 

-  Studies of the cellular and molecular effect of environmental toxins on
alterations in oxidative stress, increased mitochondrial mutations and
dysfunction and altered protein metabolism including the metabolism of
?-synuclein and parkin. 

-  Toxicant-induced paradigms for studying the mechanism of formation and the
role of Lewy body and Lewy body-like inclusions and the comparisons of these
structures with those seen in idiopathic PD.

-  Studies on the role of inflammatory processes in toxicant-induced PD. 

-  Xenobiotics' potential influence on programmed cell death, neural
plasticity, or other processes critical to the maintenance of neuronal
viability and function.

-  Potential role of dietary and life style factors, e.g., fat, fiber, iron,
antioxidants, alcohol, caffeine, and tobacco as either predisposing or
preventive influences.

-  Studies on the disruption of dopamine function in the substantia nigra by
environmental contaminants.

Applications that are collaborations between basic, clinical neuroscientists,
and neurotoxicologists and/or interdisciplinary in nature are especially
encouraged. 

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 sub populations 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 available on the web at the following URL address:    
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.  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.

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
and facsimile numbers of the Principal Investigator, the identities of other
key personnel and participating institutions, and the number and title of this
RFA.  Although a letter of intent is not required and is not binding, and does
not enter into the review of a subsequent application, providing it is highly
encouraged.  The information it contains will allow NIH staff to estimate the
workload and avoid potential conflicts of interest in the review process
planning.

The letter of intent is to be sent by to Dr. Linda Bass at the NIEHS at the
address given below by the letter of intent receipt date listed at the heading
of this RFA.

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. 

They may also be downloaded from the Internet at:
http://grants.nih.gov/grants/funding/phs398/phs398.html

Specific application instructions for this RFA have been modified to reflect
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being offered 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

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.  Please note,
however, that the Principal Investigator should be prepared to budget for
travel funds up to $2000 to attend an annual meeting of the grantees if an 
award is made.  The meeting will be coordinated by NIEHS/NINDS Program
Officials for the express purpose of sharing research progress and goals.  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.  In preparing Modular Grant Applications, the standard instructions for 
specific award mechanisms should be generally followed: (R01 and R21), with
these specific modifications reflecting modular budget and just-in-time
concepts:

Modular Grant applications must 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 PHS398
application instructions and not be formatted as a modular grant application. 
The total direct costs must be requested in accordance with the program
guidelines for the individual R01 or R21 mechanism described in this RFA. 

The formatting must follow 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. Provide an additional narrative budget
justification for any variation in the number of modules requested.

o  Personnel - 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.

o  Consortium/Contract Costs - 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.

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, for
ongoing research projects and those completed during the last three years, and 
- list selected peer-reviewed publications, with full citations.

o  Other Support - Do not submit the 'other support' pages.  Selected other
support relevant to the proposed research may be included in the Biographical
Sketch as indicated above.  Complete other support information will be
requested by the staff of NIEHS or collaborating Institutes if there is a
possibility for an award.

o  Checklist - This page should be completed and submitted with the
application.  If an 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  Page Limitation - Page limitations for the R01 applications are as stated
for the PHS 398 instructions for this mechanism.  In keeping with the
exploratory/development nature of the R21 mechanism, the application (aims,
background and significance, preliminary data and experimental design and
methods) is limited to 20 pages.  Tables and figures are included in the 
20-page limitation.

o  Appendix - An appendix or additional supporting materials will not be
accepted with the exception of originals of photos used in the application.

o  Contact - 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. 

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

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.

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:

Linda K. Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Division of Extramural Research & Training
National Institute of Environmental Health Sciences
PO Box 12233,  MD EC-24
Research Triangle Park, NC  27709
Telephone: (919) 541-1307
Fax: (919) 541-2503
email: bass@niehs.nih.gov

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIH.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.

An appropriate peer review group convened by the NIEHS in accordance with the
review criteria stated below will evaluate applications that are complete and
responsive to the RFA for scientific and technical merit. As part of the
initial merit review, a process may be used by the initial review group in
which applications 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 and assigned
a priority score. The scored applications will receive a second level review
by the Institutes 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:

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.

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

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.  The initial review group will also examine the
provisions for the protection of human subjects and the safety of the research
environment.

SCHEDULE

Letter of Intent Receipt Date:          November 5, 1999
Application Receipt Date:               January 11, 2000
Peer Review Date:                       March, 2000
Council Review:                         May, 2000
Earliest Anticipated Start Date:        July 1, 2000

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  Scientific merit (as determined by peer review);
o  programmatic priorities, and 
o  availability of funds.


INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.  Direct inquiries regarding R01 and R21
programmatic issues to:

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
Email: kirshner@niehs.nih.gov

Eugene J. Oliver, Ph.D.
Division of Stroke, Trauma and Neurodegenerative Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue,  Room 806
Bethesda, MD 20892
Telephone: (301) 496-5680                         
FAX: (301) 480-1080
Email: eo11c@nih.gov

Direct inquiries regarding fiscal matters to:

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                                  

Mary Graham
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue,  Room 806
Bethesda, MD 20892
Telephone: (301) 496-9231                         
FAX: (301) 402-0219
Email: pd23n@nih.gov


AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.113 and 93.866. 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 Part 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, and 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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