NIH GUIDE, Volume 22, Number 7, February 19, 1993

PA NUMBER:  PA-93-54

P.T. 34


  Neuromuscular Disorders 

  Biology, Cellular 



  Cell Lines 

  Disease Model 

National Institute of Neurological Disorders and Stroke


The National Institute of Neurological Disorders and Stroke (NINDS)

invites research grant applications seeking support of a wide

spectrum of research directed at generating improved knowledge

concerning amyotrophic lateral sclerosis (ALS).

ALS is a progressive fatal neuromuscular disease, the prototype and

most common disorder in the class of motor neuron diseases.  In this

disorder of unknown cause, motor neurons of the brain and spinal cord

degenerate, leading to muscle atrophy and progressive paralysis.

Subtypes of the disease are defined by location of damage, as in

progressive bulbar palsy, or preferential involvement of upper or

lower motor neuron, as in primary lateral sclerosis or spinal

muscular atrophy.  There is no known treatment that will prevent,

reverse, or otherwise alter the course of the disease.  The basic

pathogenetic mechanisms of the disease are also unknown.

On a worldwide basis, ALS affects five to seven persons per 100,000.

The disease strikes about 1.5 times as many men as women. It is

estimated that some 13,000 to 20,000 Americans have ALS.  Five to ten

percent of all cases are familial, usually inherited in an autosomal

dominant pattern, and affect roughly half of family members.

Prevalence studies indicate about 5,000 new cases of ALS in the U.S.

each year.  The most common form of ALS in the U.S. is sporadic.

Familial and sporadic ALS are clinically undistinguishable.  The

disease commonly strikes in the fifth through seventh decades of

life, although cases in young adults and in the elderly are well

recognized.  The average duration of life after onset of symptoms of

ALS is three years, encompassing a progressive course of increasing

disability.  Ninety percent of patients die within five years.

Progress and achievements in brain and nervous system research

culminated in the Congressional House resolution and Presidential

Proclamation declaring the Decade of the Brain (1990s).  NINDS's

Implementation Plan pointed out unsolved problems, and offered

recommendations for significant and profitable research areas to

pursue.  In support of these recommendations, NINDS is issuing this

program announcement soliciting grants from individuals in all

disciplines for support of research into the etiology and

pathogenesis of ALS, and in research areas that are directly and

indirectly relevant to ALS.


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 program

announcement, Amyotrophic Lateral Sclerosis, is related to the

priority area of chronic disabling diseases.  Potential applicants

may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.

017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by foreign and domestic institutions,

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.

Applications from minority institutions, minority individuals, and

women are particularly encouraged.  Foreign institutions are eligible

for  research project grants (R01) and individual National Research

Service Awards (F32) only.  Only  citizens and permanent U.S.

residents may apply for K04, K08, F32, and T32 awards.


Research support may be requested through application for an

individual investigator-originated research project grant (R01).

Applications from new investigators who have not received previous

PHS research grant support may apply for a First Independent Research

Support and Transition (FIRST) award (R29).  To apply for the support

of a more broadly based multidisciplinary research program, the

research program project (P01) mechanism is suggested.  NINDS also

provides support for the career development of clinical investigators

through Clinical Investigator Development Award (K08), and

development of young scientists through Research Career Development

Awards (K04),  Individual National Research Service Awards

(fellowships) (F32), and Institutional National Research Service

Awards (T32).


The etiology of ALS is unknown.  There is no effective treatment for

this disease.  Clinical features of the disease are well described.

A number of pathological, biochemical, and electrophysiological

abnormalities are recognized in affected patients and appreciated in

post-mortem nervous tissues.  Markers for genes in familial ALS, both

dominant and recessive, have been found, but they represent only a

portion of the possible gene loci.  Further genetic studies of ALS

linked to other chromosomes are needed.  There is opportunity for

increased research effort on the abnormal biology of the affected

motor neuron, on CNS response to endogenous and environmental toxins,

and on identification of metabolic, endocrine, and immunological

abnormalities.  There is an urgent need for expansion of research on

development of new approaches to therapy and the creation of useful

new animal models.  Because of scarcity of information on mechanisms

of the disease, the NINDS encourages individuals from all relevant

disciplines to submit grant applications.

Examples of research goals, many of which could be studied in humans

as well as animal models and tissue culture, and appropriate for

pursuing an application in response to this announcement, include,

but are not limited to:

o  Continuation and expansion of the studies of the natural history

of the disease.  Studies of the ALS patient may shed light on

potential environmental and other cause(s) of the disease.  Studies

of other disorders of motor neurons which may simulate ALS and shed

light upon its variants in cause and expression.

o  Studies of involvement in the etiopathogenesis of ALS of

endogenous agents, such as excitatory amino acids, and exogenous

agents, such as environmental or occupational toxicants.

o  Identification and mechanistic studies of chemical agents which

protect motor neurons after injurious procedures or exposures;

identification and characterization of novel neurotrophic factors

that promote neuronal development, neuronal survival, recovery, and

repair.  These studies may be relevant to our understanding of ALS

and development of potential new therapies.

o  Identification and characterization of genes involved in ALS.

Some familial forms of ALS have been linked to chromosome 21, and it

is likely that involvement of other genes may be identified as well.

o  Cell biological studies of the motor neuron, as well as other

nervous and non-nervous system cells.  Specifically, identification

and characterization of molecules expressed exclusively or

preferentially on or by motor neurons, and elucidation of their

function, and possible relevance to ALS.

o  Studies of anterograde and retrograde axonal and transsynaptic

transport, seeking specific carriers, receptors, or ion channels

specific to motor neurons that could explain cause(s) of the motor

neuron's selective vulnerability in ALS.

o  Experimental therapeutic research and conduct of well designed

controlled clinical trials.

o  Establishment of immortalized cell lines with motor neuron

specific properties.

o  Development of new experimental animal models of the disease.

Identification and description of natural animal models of ALS could

be especially beneficial in generating model systems for therapeutic

intervention, and would allow the conduct of pathophysiological and

experimental studies otherwise impossible to perform in humans.

o  Epidemiological and demographic studies of ALS, especially of high

risk populations.





NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and

women in study populations so that research findings can be of

benefit to all persons at risk of the disease, disorder, or condition

under study. Special emphasis should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders,

and conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.

The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information should be included in the form PHS 398

in Sections 1-4 of the Research Plan AND summarized in Section 5,

Human Subjects.  Applicants are urged to assess carefully the

feasibility of including the broadest possible representation of

minority groups.  However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaska

Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale

for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders, or conditions, including, but not limited to,

clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed and the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these



To apply for R01, R29, P01, K04, K08, and T32 grant applications,

form PHS 398 (rev. 9/91) is to be used, and for F32 form PHS 416-1 is

to be used. Additional instructions and substitute pages are included

with the PHS 398 kit for K04 and T32.  Application receipt dates for

R, K, and P grants are:  February 1, June 1, October 1; for T grants:

January 10, May 10, September 10; and for F grants: April 5, August

5, December 5. "NINDS Application Guidelines for Program Project

(P01) and Center (P50) Grants" (rev. 4/92), and guidelines for K

awards are available upon request from the Program Administrator

identified below.

Application kits are available at most institutions office of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

(301) 496-7441.

On the first (face) page, item 2a, of the application, the word "yes"

must be checked and the title and number of the announcement typed in

the space provided:  "Amyotrophic Lateral Sclerosis" PA-93-54.

The original and five copies of the PHS 398 application or two copies

of PHS 416-1 must be sent or delivered to:

Application Receipt Office

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**

Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC as a resource for conducting

the proposed research.  If so, a letter of collaboration from the

GCRC Program Director or Principal Investigator should be included

with the application.


Applications received under this PA will be assigned to the Initial

Review Group (IRG) in accordance with established PHS referral

guidelines.  The IRGs, which are composed primarily of non-federal

scientific and technical experts, will review the applications for

scientific and technical merit.  Following IRG review, the

applications will receive a second-level review by one or more

appropriate advisory councils.


The standard review criteria will be used to assess the scientific

merit of applications.

Applications will compete for available funds with all other

applications.  The following will be considered when making funding


o  Quality of the proposed projects as determined by peer review;

o  Availability of funds;

o  Program balance among research areas.


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. A. P. Kerza-Kwiatecki

Division of Demyelinating, Atrophic, and Dementing Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 804

7550 Wisconsin Avenue

Bethesda, MD  20892

Telephone:  (301) 496-1431

FAX:  (301) 402-2060

Direct inquiries regarding fiscal matters to:

Ms. Laura Williams

Division of Extramural Activities

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

7550 Wisconsin Avenue

Bethesda, MD  20892

Telephone:  (301) 496-9231

FAX:  (301) 402-0219


This program is described in the Catalog of Federal Domestic

Assistance No. 93.853 and 93.854.  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 PHS grants policies and Federal

Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 or Health Systems Agency review.


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