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

PA NUMBER:  PA-92-47

P.T. 34



  Biology, Cellular 

  Molecular Genetics 


  Disease Model 

National Institute of Neurological Disorders and Stroke

National Cancer Institute


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

the National Cancer Institute (NCI) encourage the submission of

research grant applications in basic science and clinical

investigations concerning all aspects of neurofibromatosis including

molecular genetics, cell biology, pathophysiology, development of new

animal models, diagnosis, and treatment.


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, Neurofibromatosis, is related to the priority areas of

chronic disabling conditions and cancer.  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).


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 to apply for the First

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


Applicants may use the Research Project Grant (R01), Research Program

Project (P01), Research Center Grant (P50), and FIRST Award (R29).

Prospective applicants are encouraged to communicate with the NINDS and

NCI program contacts listed at the end of the announcement regarding

the appropriate funding mechanism.


Neurofibromatosis 1 (NF1), or von Recklinghausen's disease, is an

autosomal dominant inherited disorder affecting the central and

peripheral nervous system.  Its prevalence is about 1 in 4,000.  It is

characterized by cafe au lait spots of the skin, neurofibromas,

schwannomas, intracranial tumors, Lisch nodules, and other associated


The NF1 gene on chromosome 17 has been cloned.  Further studies are

needed to characterize its gene product.  The normal NF1 gene product

may be an anti-oncogene that suppresses the ras oncogene.  When

disinhibited by the mutation of the NF1 gene, the ras oncogene may

cause tumor formation.

At the present time, molecular genetic screening is of limited

usefulness in counseling and clinical management of NF1.  It requires

familial markers (not available for all families or for sporadic

cases), and it cannot predict the rate or degree of progression of the

disorder in a given diagnosed individual.

Neurofibromatosis 2 (NF2), or bilateral acoustic neurofibromatosis, is

an autosomal dominant disorder associated with vestibular schwannomas

and other schwannomas, meningiomas, ependymomas, gliomas, and posterior

subcapsular cataracts.  Its prevalence is about 1 in 40,000.

The NF2 gene has been mapped to chromosome 22 in one published family.

The gene has not yet been isolated.  It is believed to normally

function as a tumor suppressor gene.

Multidisciplinary and collaborative studies of neurofibromatosis are

encouraged.  Examples are given below, but applications are not limited

to these areas of research:

o  Improvement of diagnostic criteria and tests for use in genetic

counseling and clinical management of NF1, NF2, and atypical or variant


o  Development of transgenic animal models to study the pathogenesis of

NF1, NF2, and associated tumors.

o  Studies to explain the variability of clinical expression of NF1 and

NF2.  Can genotype-phenotype correlations be made in an individual

patient?  Is the phenotype modulated by modifying genes?  Does the

expression of these disorders in a given individual depend not only on

the precise genetic defect but also on the individual's sex, on the

parent from whom the gene defect was inherited, or on other factors?

o  Identification and analysis of the NF1 and NF2 gene products and

their functions in normal cellular physiology, in the pathophysiology

of neurofibromatosis, and in tumorigenesis.

o  Basic studies of neurodevelopmental mechanisms affected by

neurofibromatosis such as neural crest cell migration and


o  Understanding the nature and neurobiologic basis of the cognitive

impairment associated with NF1.

o  Development and assessment of new and innovative therapeutic

strategies for the many associated manifestations of NF1 and NF2.





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


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.


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

"Neurofibromatosis, and PA-92-47."

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," or the NCI pamphlet,

"Program Project Grant of the National Cancer Institute," which 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**


Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications will be judged on scientific

merit and program relevance 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 national advisory



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


For further information regarding this announcement, potential

applicants may write or call:

Philip H. Sheridan, M.D.

Developmental Neurology Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 8C10

Bethesda, MD  20892

Telephone:  (301) 496-6701


Michael R. Martin, Ph.D.

The Tumor Biology Program

National Cancer Institute

6120 Executive Plaza South, Room 630

Rockville, MD  20852

Telephone:  (301) 496-7028

For fiscal and administrative inquiries 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


Robert Hawkins

Grants Administration Branch

National Cancer Institute

6120 Executive Plaza South, Room 243

Rockville, MD  20852

Telephone:  (301) 496-7933


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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