THE HEREDITARY ATAXIAS INCLUDING MACHADO-JOSEPH DISEASE

NIH GUIDE, Volume 21, Number 9, March 6, 1992



PA:  PA-92-48



P.T. 34



Keywords:

  Genetics 

  Pathophysiology 

  Molecular Genetics 

  Diagnosis, Medical 

  Epidemiology 



National Institute of Neurological Disorders and Stroke



PURPOSE



The Convulsive, Developmental, and Neuromuscular Disorders Program of

the National Institute of Neurological Disorders and Stroke (NINDS)

encourages the submission of applications for research grants related

to the hereditary ataxias including Machado-Joseph Disease (MJD).  The

NINDS invites grant applications to support research on all aspects of

this heterogeneous group of inherited degenerative disorders including

pathophysiology, epidemiology, molecular genetics, diagnosis, and

treatment.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention goals of "Healthy People 2000," a

PHS-led national activity for setting priorities.  This program

announcement, The Hereditary Ataxias Including Machado-Joseph Disease,

is related to the priority areas of physical activity and fitness, and

chronic disabling conditions.  Potential applicants may obtain a copy

of "Healthy People 2000" (Full Report:  No. 017-001-474-0, or 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, 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 individuals and women are encouraged.

However foreign institutions are not eligible for the First Independent

Research Support and Transition (FIRST) Award (R29).



MECHANISMS OF SUPPORT



Applicants may use the Research Project Grant (RO1), Research Program

Project (PO1), Research Center Grant (P50), and First Independent

Research Support and Transition Award (R29).  Prospective applicants

are encouraged to communicate with the NINDS program contact listed at

the end of the announcement regarding the appropriate funding

mechanism.



RESEARCH OBJECTIVES



The hereditary ataxias, in general, encompass a variety of degenerative

disorders, interchangeably referred to as spinocerebellar

degenerations, that are difficult to classify due to limited knowledge

of etiologic factors, variability of clinical manifestations, and

limited correlation between clinical signs and postmortem changes.

Onset of system degenerations may span a lifetime but often begin in

the first to second decade of life.



In the past, the hereditary ataxias have been categorized into

predominantly spinal, spinocerebellar, and pure cerebellar forms based

on a "typical" clinical picture and age of onset of signs and symptoms.

Familial inheritance has been clearly shown in many of these disorders,

and families may exhibit x-linked recessive, autosomal dominant or

recessive patterns.



The predominant presentation is the development of a chronic,

progressive ataxia with variable signs and symptoms referable to the

cerebellum and its afferent and efferent pathways, posterior columns,

pyramidal tracts, basal ganglia, brainstem nuclei, other brain regions

and peripheral nerve.  In addition, there may be visual impairment

(optic atrophy, pigmentary retinal degeneration), hearing dysfunction

(sensory neural hearing loss), dermatological manifestations,

hypogonadism, dementia, and, in some disorders, definable biochemical

or genetic abnormalities.



Though the clinical picture may be consistent within a family, there

may be gradations of presentation that result in overlap and somewhat

arbitrary distinctions, between disease entities.  Examples of diseases

addressed in this announcement include MJD, hereditary spinocerebellar

ataxias (Friedreich's Syndrome), hereditary cerebellar ataxias,

ataxia-telangiectasia, hereditary spastic paraplegia, Roussy-Levy and

Marinesco-Sjogren syndrome, abetalipoproteinemia (Bassen-Kornzweig

syndrome), Refsum's disease and dyssynergia cerebellaris myoclonica

(Ramsay Hunt syndrome).  One representative example of the hereditary

ataxias, MJD, is an autosomal dominant, hereditary, progressive motor

system disease initially identified among families of

Portuguese-Azorean descent but now identified worldwide in many ethnic

groups.  Three main syndromes have been described based on

heterogeneity of clinical expression felt to be phenotypic

variabilities of a single gene mutation.  The progressive neurological

deficits result in death from debilitation within 10 to 30 years of

onset.  To date, there is no genetic or biochemical marker.  There is

no effective treatment or cure.  Prevention depends on limited genetic

counseling of identified families.



In June 1991 an NINDS-sponsored international workshop on Research

Initiatives on Machado-Joseph Disease explored issues on the

description of the clinical spectrum and epidemiology, neuropathology

and neurochemistry, molecular genetics, and improving diagnosis and

treatment.  Research needs and priorities include more precise

diagnosis, elucidation of the pathophysiology, molecular genetics, and

treatment of this, and similar ataxic disorders.



The goals of this announcement are to stimulate research in both basic

science and clinical aspects related the hereditary ataxias including

MJD.  The scope of this program encompasses both animal and human

studies that would utilize a variety of experimental approaches and

methods.  A major emphasis is to expand research of the underlying

mechanisms of early brain degeneration inherent to each of the

hereditary ataxias.  Multidisciplinary and collaborative studies are

encouraged.  Examples of areas of potential research include, but are

not limited to, the following:



o  Standardized definitions and diagnoses:  research criteria and

classifications.



o  Longitudinal studies that describe the natural history of disease

and that provide complete descriptions of clinical signs and symptoms

of disease within families.



o  Neuroepidemiological studies of at-risk populations.



o  Experimental animal models with cerebellar system degenerations that

have features consistent with neuropathological changes of the

disorder.



o  Collaborative neuropathological studies on affected and at-risk

populations utilizing a variety of techniques that better identify the

first cells to be affected, the progression of the disease, and the

type of dysfunction that occurs in those cells prior to death.



o  Evaluate possible therapeutic interventions to retard the

progression of disease.



o  Neurochemical studies to define pathophysiology and to enable

premorbid diagnosis or risk determination.



o  Studies utilizing neurodiagnostic and neuroimaging modalities.



o  Collaborative efforts on genetic research with an interchange of

families, probes, and results towards identifying the defective gene(s)

and gene products.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 must 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 must 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 must be included in the form PHS 398 in

Section 2, A-D of the research plan AND summarized in Section 2, E,

Human Subjects.  Applicants/offerors 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 Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for studies

on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as 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



Applications are to be submitted on the grant application form PHS 398

(rev. 9/91) according to instructions contained in the application kit.

Application kits are available from most institutional business offices

and may be obtained from the Office of Grants Inquiries, Division of

Research Grants, Westwood Building, Room 449, National Institutes of

Health, Bethesda, MD 20892, telephone 301-496-7441.



Check "yes" in item two on the face sheet of the application and type

"The Hereditary Ataxias Including Machado-Joseph, PA-92-48."



Applicants for the P01 or P50 must use the application format as

described in the NINDS pamphlet, "Application Guidelines: Program

Project and Clinical Research Center Grants," that may be obtained from

the contacts listed under INQUIRIES.



Deadlines for the receipt of applications are February 1, June 1, and

October 1.  The completed original application and five legible copies

must be sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications will be judged on scientific

merit in accordance with NIH policy and procedures involving peer

review.  An initial review will be made by an appropriate study section

of the Division of Research Grants for research grants and FIRST

awards, and by an appropriate Institute or Center committee for program

project and center applications.  A second level of review will be made

by an appropriate advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be used in making funding decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement



INQUIRIES



For further information regarding this announcement, potential

applicants may write or call:



Giovanna M. Spinella, M.D.

Developmental Neurology Branch

Division of Developmental, Convulsive, and Neuromuscular Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 820

Bethesda, MD  20892

Telephone:  (301 496-5821



For fiscal and administrative inquires regarding this announcement,

potential applicants may write or call:



Gary P. Fleming, J.D

Grants Management Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

Bethesda, MD  20892

Telephone:  (301) 496-9231



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

No. 93.853, Clinical Research Related Neurological Disorders and

93.854, Biological Basis Research in the Neurosciences.  Awards are

made under authorization of the Public Health Service Act, Title IV,

Part A (Public Law 78-410, as amended by Public Law 99-150, 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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