RELEASE DATE:  August 6, 2003

PA NUMBER:  PAS-03-160 (Expiration date changed, see NOT-ES-06-006)
                       (see NOT-ES-04-009)
EXPIRATION DATE:  March 2, 2006, unless reissued.

National Institute of Environmental Health Sciences (NIEHS) 



o Purpose of the PA
o Background
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


There is provocative evidence that environmental exposures to certain 
neurotoxicants (heavy metals, pesticides and fungicides) may play a role in 
the development of neurodegenerative movement disorders such as Parkinson's 
disease (PD) and amyotrophic lateral sclerosis (ALS).  Recent research in 
these diseases has focused on both the underlying biological processes 
critical to disease manifestation for the development of new treatments and 
on the relative roles of environmental, endogenous neurochemical and genetic 
factors in their etiologies.  Much work, however, remains to be done to 
clarify these fundamental processes.

The objective of this three-year Program Announcement (PA) is to stimulate 
research on the relative roles of environmental, endogenous neurochemical and 
genetic factors in the causation of neurodegenerative diseases.  In previous 
years, the NIEHS has focused its efforts on the expansion of research in 
Parkinson's disease culminating in the establishment of Collaborative Centers 
for Parkinson's Disease Environmental Research (See This new initiative will 
selectively shift its research focus each year to emphasize a different 
neurodegenerative disease.  In the current year, the special focus is to 
mainly solicit research on gene-environment interactions as a risk factor in 
ALS (a fatal disease of unknown etiology marked by the progressive 
degeneration of motor neurons) in order to stimulate much needed research in 
this area.  In succeeding years, there will be an announcement indicating a 
different neurodegenerative disease focus area. 


Several epidemiological studies have implicated gene/environment interactions 
in the development of PD and ALS.  Nevertheless, it is still not clear 
whether differences in prevalence rates or clusters of these diseases in 
various communities are due to the differential distribution of a 
hypothetical environmental toxicant or are more frequent where a familial 
heritable defect is more common.  To date, 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 some investigators.  

While a good deal of research has been devoted to the influence of the 
environment in the susceptibility to PD, there has not been a similar effort 
committed to ALS.  In ALS the motor neurons of the brain and spinal cord are 
primarily targeted to degenerate, leading to muscle atrophy and progressive 
paralysis while cognitive function is usually unimpaired.  No treatment is 
currently available that will prevent, reverse, or otherwise alter the course 
of the disease nor are the basic pathogenetic mechanisms of the disease 
known.  On a worldwide basis, ALS affects five to seven persons per 100,000, 
striking about 1.2 times as many men as women.  Around 30,000 Americans have 
ALS.  About 10 percent of all cases are believed to be familial, usually 
inherited in an autosomal dominant pattern, and affecting roughly half of 
family members.  Prevalence studies indicate about 5,000 new cases of ALS in 
the U.S. each year, 90 percent of which are sporadic.  Familial and sporadic 
ALS (SALS) appear to be clinically undistinguishable.  The disease commonly 
strikes in the fifth through seventh decades of life, although cases in young 
adults and in the elderly are known.  The average duration of life after 
onset of symptoms of ALS is around three years, encompassing a progressive 
course of increasing disability.


Some progress has been made in recent years toward understanding the 
biological bases of ALS.  A number of pathological, biochemical, and 
electrophysiological abnormalities are found in affected patients and are 
seen in post-mortem nervous tissues.  Markers for genes in familial ALS 
(FALS), both dominant and recessive, have been identified, but they represent 
only a portion of the possible gene loci.  Fifteen to 20 percent of FALS have 
a mutation of the copper/zinc superoxide dismutase (SOD1) gene on chromosome 
21.  However, the overwhelming majority of ALS patients do not have this 
mutation.  Genetic studies of ALS linked to other chromosomes are needed 
especially of those genes easily influenced by neurotoxicants.

It is significant that the first descriptions of ALS coincided with the 
industrial revolution.  Therefore, it has been logical to consider whether 
environmental contamination associated with increased levels of industrial 
activity might be implicated in its pathogenesis.  The possible role of 
occupational exposures in ALS has also been investigated.  Epidemiological 
studies have implicated heavy metals and other environmental exposures as 
risk factors for ALS but as yet have not provided a clear directional lead.  
For example, various studies have looked at occupational exposure to lead, 
mercury, selenium, manganese, aluminum, and iron exposure in assessing risk 
factors for the disease.  Calcium has also been studied because of 
suggestions that excitotoxicity and calcium channel antibodies may be 
implicated in its etiology.  In addition, in some areas, agricultural workers 
seem to have a higher risk of developing ALS, while studies on the exposure 
to industrial solvents and chemicals have brought mixed results.  No coherent 
picture has emerged from these studies nor have many of them been correlated 
with genetic studies.  Therefore, much remains to be learned about the 
mechanisms through which genetic mutations and other biological insults lead 
to pathology.  Consequently, research on the response to endogenous and 
environmental toxicants, on the abnormal biology of the affected motor and 
non-motor neurons, and on the identification of metabolic, endocrine, and 
immunological abnormalities needs to be expanded. 

The genetic defects identified in the familial form of ALS have lead to the 
development of some useful animal models of the disease but more models are 
needed to expand research on the abnormal biology of the affected motor 
neuron and nonneuronal cells, on nervous system response to endogenous and 
environmental toxins and toxicants, and on identification of metabolic, 
endocrine, and immunological abnormalities. 

Several meetings focused on ALS have categorized fruitful mechanistic 
approaches to studying ALS.  These are (1) the role of mitochondrial 
oxidative stress, (2) the role of calcium/excitotoxicity, (3) the role of 
proteosomal dysfunction and (4) the role of cytoskeletal dysfunction.

Additional research is also needed to understand the contribution of 
environmental exposure, endogenous susceptibility factors, and increasing age 
in the disease linkage.  This will require a concurrent advancement and 
refinement of methodologies and sciences.  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 that can serve as 
a cogent guide to underlying cellular and molecular mechanisms in humans.

This initiative will seek to solicit novel approaches to understanding ALS, 
with emphasis on how gene-environment interactions may play in the above.  
Examples of research goals that could be pursued, especially in appropriate 
animal models and tissue culture, are listed below.

o Development of animal models of ALS especially nonmammalian models useful 
for gene/environment research.
o Development of biomarkers of exposure/disease in animal models 
(metabonomics, etc.)
o Research on modifier genes and environmental influences in animal models. 
o Studies on the intersections/synergies between genetic susceptibilities and 
environmental factors, as well as strategies for identifying putative 
toxicants and other environmental factors involved in the etiology of ALS.
o Establishment of disease incidence and variation according to age, gender, 
race/ethnicity, geography, exposure.
o Studies on potentially informative clusters  (Western Pacific ALS/PDC, 
Persian Gulf War ALS, Kelly Air Force, etc.)
o Studies on occupational/environmental exposures and non-occupational 
exposures (evidence for role of metals, pesticides, solvents, 
residential/avocational exposures, tobacco, alcohol, infectious agents.)
o Research on the potential role of dietary excitotoxins in Western Pacific 
ALS-PDC-Dementia; analogies with other disorders.
o Research on the role of dietary intake of antioxidants, minerals (copper, 
zinc, iron) and the association of fat and fiber intake with ALS.
o Research on factors targeting putative environmental toxicants specific to 
motor neurons and surrounding cells including muscle cells.
o Research on disease mechanisms on cellular/subcellular level (oxidative 
stress, excitotoxicity, apoptosis) from neurotoxic exposures.
o Evaluation of retrograde axonal transport of toxins to the spinal motor 
neurons and their response (access and possible uptake of toxic substances at 
the neuromuscular junction.)

The above is not intended to be all-inclusive.  Moreover, the NIEHS would 
like to encourage multidisciplinary and interdisciplinary studies.  What may 
be especially useful are collaborations with ongoing research in other motor 
disorder diseases that could be expanded to include ALS studies.  We also 
encourage the use of novel animal models such as drosophila, zebra fish and 
C. elegans, as well as newly available technologies.  Especially useful would 
be collaborative pooling of resources to standardize epidemiological 
instruments, microarray analyses, -omics technologies, etc, for meaningful 
use among several laboratories.


This PA primarily will use the NIH Research Project Grant (R01) and   
Exploratory/Developmental Grant (R21) award mechanisms (though, if 
appropriate, competitive supplements may be considered if it is to accomplish 
collaborations.)  As an applicant, you will be solely responsible for 
planning, directing, and executing the proposed project.  This PA uses just-
in-time concepts.  It also uses the modular as well as the non-modular 
budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at  


The NIEHS intends to commit approximately $2M in FY 2004 to fund 10-15 new 
grants in response to this PA.  An applicant may request a project period of 
up to five years for R01s and up to two years for R21s.  Direct costs for 
R21s may not exceed $275,000.  The characteristics, requirements, 
preparation, and review criteria for R21 applications are described at  Because the 
nature and scope of the proposed research will vary from application to 
application, it is anticipated that the size and duration of each award will 
also vary.  Although the financial plans of the NIEHS provide support for 
this program, awards pursuant to this PA are contingent upon the availability 
of funds and the receipt of a sufficient number of meritorious applications.  


You may submit (an) application(s) if your institution has any of the 
following characteristics:
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas: scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Annette Kirshner, Ph.D.
Program Administrator
Cellular, Organs and Systems Pathobiology Branch 
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD-23
Research Triangle Park, NC 27709
Telephone:  (919) 541-0488
FAX:  (919) 541-5064

o Direct your questions about financial or grants management matters to:

Pamela Evans
Grants Management Specialist
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD-22
Research Triangle Park, NC 27709
Telephone:  (919) 541-7629
FAX:  (919) 541-2860


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at  Application 
deadlines are also indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least six weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types.  Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the National Advisory Environmental Health 
Sciences Council.  


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:

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  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.

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?  

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  


BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001
a complete copy of the updated Guidelines are available at
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy 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 is available at

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see  
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at

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.  Furthermore, 
we caution reviewers 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 
PA is related to one or more of the priority areas.  Potential applicants may 
obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
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