MULTIPLE SCLEROSIS

NIH GUIDE, Volume 22, Number 2, January 15, 1993



PA NUMBER:  PA-93-38



P.T. 34



Keywords:

  Neuromuscular Disorders 

  Etiology 

  Pathogenesis 



National Institute of Neurological Disorders and Stroke



PURPOSE



The National Institute of Neurological Disorders and Stroke (NINDS),

a component of the National Institutes of Health, invites research

grant applications seeking support of a wide spectrum of research on

multiple sclerosis.



Multiple sclerosis (MS) is one of the most common neurological

disorders of young adults.  It has been estimated that there are

about 250,000 to 300,000 MS patients in the U.S., and some 200 new

cases are diagnosed each week.  Median duration of the disease is

over 30 years.  MS is a chronic demyelinating disease of the central

nervous system, thought to be of autoimmune pathogenesis, whose

etiology may involve genetic, viral, and immunological factors.

Affected patients may exhibit neurological abnormalities such as

visual and other sensory disturbances, and partial or complete

paralyses.  The course of the disease may vary from relapsing-

remitting to a chronic-progressive course.  Because this disabling

disease, without effective treatment, afflicts young adults with near

normal life expectancy, the cost of medical care, including patient

rehabilitation and loss of productivity, represent an economic burden

estimated to be in excess of $2.5 billion annually.



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 MS, and in research areas that are directly and

indirectly relevant to MS.



HEATHY 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 Program

Announcement (PA), Multiple 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).



ELIGIBILITY REQUIREMENTS



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 not

eligible for R29, P01, K04, K08, F32, and T32.



MECHANISM OF SUPPORT



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).



RESEARCH OBJECTIVES



There are a number of research directions whose exploration may shed

new light on understanding the causation, pathogenesis, diagnosis,

and potential treatment of this important chronic disease.  This

program announcement seeks to stimulate and encourage ideas that can

compete successfully for support through grants-in-aid from NINDS.

Examples of research goals, many of which may lend themselves to

study in man as well as in animal models and in in vitro systems,

that may be considered for research grant applications in response to

this program announcement would include, but are not limited to, the

following:



o  Further genetic studies of the human disease and its animal models

are needed.  There is some limited evidence in humans that there is a

predilection to the development of MS in individuals with a

particular genetic makeup.  A familial tendency is noted with

moderate risk increases in twins and first degree relatives of index

cases.  There are significant variations in MS prevalence in various

ethnic groups and geographic variation in the disease.  In animal

model disorders such as Experimental Autoimmune Encephalomyelitis,

there is very pronounced evidence of genetic factors of

susceptibility and resistance.



o  Genetic, hormonal, and other innovative studies are needed to

elucidate the reason(s) for the pronounced susceptibility of women to

this disorder and/or the relative sparing of men.



o  Cell biological studies of normal and pathological functions and

interactions of oligodendroglia, myelin, and neurons are needed to

shed light on mechanisms of demyelination and remyelination in MS.



o  There is a need for further studies of protein and lipid synthetic

mechanisms in myelin assembly.  Knowledge of mechanisms controlling

transcription and translation of proteins, limiting enzymes, lipid

pathways, and myelin maintenance could give new information into the

control and pathways of demyelinating disorders.



o  Studies are encouraged on cytokine expression during phases of MS,

including studies of cytokine activity in plaque material and in

cerebrospinal fluid during active and quiescent phases of the

disease.



o  The bases of central nervous system inflammation as precursor or

companion of demyelination deserve further study.  Examples of active

research include studies of lymphocyte trafficking in relation to

blood-brain-barrier, studies of cell adhesion and other recognition

molecules, and studies of heat shock protein (HSP) expression by

glial cells.  Additional studies are warranted on the role of

cellular surface and adhesion molecules in normal development and in

demyelinating disease.



o  Proposals are solicited for innovative neuroimaging methods for in

vivo studies of demyelinating disorders, including new approaches to

MS lesion quantification.  There is a special need for development of

new techniques for improved classification of MS lesions.  These

technologies could be usefully applied both in patients and in animal

model systems.



o  Further studies of viruses are needed, especially those that

initiate demyelinating diseases, utilizing primary inflammatory and

indirect immunological mechanisms, despite many years of failure to

identify a specific viral cause or single inducing antigen in humans.



o  Expansion of epidemiological and demographical studies of MS are

encouraged.



o  There is a need for rigorously designed and well controlled

clinical trials of promising new therapeutic modalities.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY 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 that 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

minorities.



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

policies.



APPLICATION PROCEDURES



Use form PHS 398 (rev. 9/91) to apply for R01, R29, P01, K04, K08,

and T32.  Additional instructions and substitute pages are included

with the PHS 398 kit for K04, K08, 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), as are guidelines

for Clinical Investigator Development Award (K08), are available upon

request from the Program Administrator identified below.



Application kits are available at most business and grants and

contracts offices and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, 5333 Westbard Avenue, Bethesda,

Maryland 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: "Multiple Sclerosis" PA-93-38.



FIRST award applications must include at least three sealed letters

of reference attached to the face page of the original application.

FIRST award applications submitted without the required number of

reference letters will be considered incomplete and will be returned

without review.



The original and five copies of the application must be sent or

delivered to:



Application Receipt Office

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



The Division of Research Grants, NIH, serves as central point for

receipt of applications.



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.



REVIEW CONSIDERATIONS



Applications received under this PA will be assigned to an Initial

Review Group (IRG) in accordance with established PHS referral

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

scientific and technical experts, will review applications for

scientific and technical merit.  Following IRG review, the

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

appropriate Advisory Councils.



AWARD CRITERIA



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

decisions:



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

o  Availability of funds;

o  Program balance among research areas.



INQUIRIES



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

Grants Management Branch, 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



AUTHORITY AND REGULATIONS



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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