RESEARCH GRANTS RELATED TO NARCOLEPSY

NIH GUIDE, Volume 22, Number 5, February 5, 1993



PA NUMBER:  PA-93-51



P.T. 34



Keywords:

  Sleep Disorders 

  Etiology 



National Institute of Neurological Disorders and Stroke

National Institute of Mental Health



PURPOSE



The Division of Convulsive, Developmental, and Neuromuscular

Disorders; National Institute of Neurological Disorders and Stroke

(NINDS) and the National Institute of Mental Health (NIMH) are

revising and reissuing a NINDS program announcement on narcolepsy

published in the NIH Guide to Grants and Contracts, Vol. 19, No. 15,

April 13, 1990, to notify the scientific community of continuing

NINDS/NIMH interest in the submission of research project grant

applications related to narcolepsy.



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 priorities.  This program

announcement is related to the priority area of narcolepsy.

Potential applicants may obtain a copy of "Healthy People 2000" (Full

Report:  No. 017-001-00474-0, or Summary Report:  Stock No.

017-001-00473-0) 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.

Foreign institutions are eligible for research project grants (R01)

only.  Applications from minority institutions, minority individuals,

and women are encouraged.



MECHANISM OF SUPPORT



The support mechanisms for grants in this area will be the

investigator-initiated research project grant (R01), the First

Independent Research Support and Transition (FIRST) award (R29), the

program project grant (P01), and the center grant (P50).  As

consistent with the aforementioned mechanisms, the Principal

Investigator or program director, as well as any participating

investigators, will plan, direct, and perform the research.

Applicants for program project grants should contact the NINDS

representative listed below as early as possible in the planning

stages.



RESEARCH OBJECTIVES



Background



Narcolepsy is a neurological condition characterized by irresistible

episodes of sleep.  The classic symptoms of narcolepsy are:  (1)

sleep attacks - sudden urges to sleep; (2) cataplexy - sudden

generalized or partial flaccid paralysis; (3) hypnagogic

hallucinations - sleep onset hallucinations; and (4) sleep paralysis

- generalized paralysis before or at the time of falling asleep or on

awakening.



Narcolepsy has its typical onset in adolescence and young adulthood.

There is an average 15-year delay between onset and correct

diagnosis, that may contribute substantially to the disabling

features of the disorder.  Cognitive, educational, occupational, and

psychosocial problems associated with the excessive daytime

sleepiness of narcolepsy have been documented.  For these to occur in

the crucial teen years when education, development of self-image, and

development of occupational choice are taking place is especially

damaging.  While cognitive impairment does occur, it may only be a

reflection of the excessive daytime somnolence.  The prevalence of

narcolepsy in the United States has been estimated to be as high as

one per 1,000.  It is a major reason for patient visits to sleep

disorder centers, and with its onset in adolescence, it is also a

major cause of learning difficulty and absenteeism from school.

Normal teenagers often already experience excessive daytime

sleepiness because of a maturational increase in physiological sleep

tendency accentuated by multiple educational and social pressures;

this may be disabling with the addition of narcolepsy symptoms in

susceptible teenagers.  In clinical practice, the differentiation

between narcolepsy and other conditions characterized by excessive

somnolence may be difficult.  Treatment options are currently

limited.  There is a paucity in the literature of controlled

double-blind studies of possible effective drugs or other forms of

therapy.  Mechanisms of action of some of the few available

therapeutic agents have been explored but detailed studies of

mechanisms of action are needed before new classes of therapeutic

agents can be developed.



The neural control of normal sleep states and the relationship to

narcolepsy are only partially understood. In humans, narcoleptic

sleep is characterized by a tendency to go abruptly from a waking

state to rapid eye movement (REM) sleep with little or no intervening

non-REM sleep.  The changes in the motor and proprioceptive systems

during REM sleep have been studied in both human and animal models.

During normal REM sleep, spinal and brainstem alpha motor neuron

hypopolarization produces almost complete atonia of skeletal muscles

via an inhibitory descending reticulospinal pathway.  Acetylcholine

may be one of the neurotransmitters involved in this pathway.  In

narcolepsy, the reflex inhibition of the motor system seen in

cataplexy is believed identical to that seen in normal REM sleep.



Despite the experimental evidence in human narcolepsy that there may

be an inherited basis for at least some forms of narcolepsy, the mode

of inheritance remains unknown.



Research Goals and Scope



The goal of this announcement is to stimulate research in both basic

and clinical aspects of narcolepsy.  The scope of this program

encompasses both animal and human studies, that would utilize a

variety of experimental approaches and methods.  If experimental

studies on human subjects are proposed, the protocols should contain

recruitment procedures to encourage the participation of women and

minorities.



Examples of areas of potential research include studies on the

pathophysiology of narcolepsy; abnormalities of circadian rhythms,

particularly anatomical and biochemical substrates; the molecular

genetics of narcolepsy; and the development of new therapies.  New,

more sensitive, and specific objective diagnostic procedures need to

be developed and validated.



While studies in the naturally occurring narcoleptic dog model

suggest an autosomal recessive mode of transmission in that model,

genetic analysis of cohorts of narcoleptic patients and

identification of informative families are needed to define the mode

of inheritance and to facilitate the search for gene markers.



STUDY POPULATIONS



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 or ethnic group.  In addition, gender and

racial or 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, the NIH recognizes that it may not be

feasible or appropriate in all research projects to include

representation of the full array of Unites States racial or ethnic

minority populations:  Native Americans (including American Indians

or Alaska Natives), Asian or Pacific Islanders, Blacks, and

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 prevention 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 or ethnic minorities when it is important to apply the results

of the study broadly.  This directive 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' population, including

minorities.



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 the NIH are

required to address these policies.  If the required information is

not contained within the application, the review will be deferred

until the information is provided. 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 the instructions included in the

application package.  These application packages are available at the

institutional office of sponsored research and 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.



Applicants for program project grants (P01) should request, from the

address below, a copy of the NINDS Guidelines:  Program Project and

Research Center Grants (rev. 6/92).  Receipt dates for new research

project grant (R01) applications and FIRST (R29) awards and for

program project (P01) and center grant (P50) applications are

February 1, June 1, and October 1.



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.



On page 1 of form PHS 398, check "yes" in Item 2a, enter the number

of this Program Announcement in the space provided, and the name of

this Program Announcement (Narcolepsy) in the blank space labeled

"Title."



Use the mailing label provided in the application package to mail the

signed original and five exact copies of it to the Division of

Research Grants.



REVIEW CONSIDERATIONS



Research project grant (R01) applications and FIRST award (R29)

applications will be reviewed for scientific and technical merit by

an appropriate study section in the Division of Research Grants.

Program project grant (P01) and center grant (P50) applications will

be reviewed according to the practice of the Institute to which the

application is assigned.  The second level of review will be by the

appropriate national advisory council.



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 quality of the proposed projects as

determined by peer review, availability of funds, and program balance

among research areas.



INQUIRIES



Questions concerning neurological/neuroscientific aspects of this

Program Announcement may be addressed to:



Charlotte B. McCutchen, M.D.

Division of Convulsive, Developmental, and Neuromuscular Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 114

Bethesda, MD  20892

Telephone:  (301) 496-6701

FAX:  (301) 402-0302



Questions concerning psychiatric aspects of the Program Announcement

may be addressed to:



Susan Blumenthal, M.D.

Basic Prevention and Behavioral Medical Research Branch

National Institute of Mental Health

Parklawn Building, Room 11C06

Rockville, MD  20857

Telephone:  (301) 443-4337

FAX:  (301) 443-4822



Questions concerning fiscal aspects of this Program Announcement may

be addressed to:



Patricia Driscoll

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 Catalogue of Federal Domestic

Assistance, Number 93.853, Clinical Research Related to Neurological

Disorders, and 93.854, Biological Basis Research in the

Neurosciences.  Grants will be awarded under the authority of the

Public Health Service Act, Title IV, Section 301 (Public Law 78-410,

as amended: 42 USC 241) and administered under PHS grants policies

and Federal Regulations 42 CFR Part 52 and 45 CFR 74.  This program

is not subject to Health Services Agency Review of the

intergovernmental review requirements of Executive Order 12372.



.

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