NEUROGENETIC DISORDERS OF INFANCY AND CHILDHOOD NIH GUIDE, Volume 23, Number 7, February 18, 1994 PA NUMBER: PA-94-035 P.T. 34 Keywords: Genetics Neuroscience National Institute of Neurological Disorders and Stroke PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS) announces the reissuance of a program announcement (originally published July 18, 1985) to notify the scientific community of continuing NINDS interest in the submission of research grant applications concerning neurogenetic disorders. 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, Neurogenetic Disorders of Infancy and Childhood, is related to the priority areas of chronic disabling conditions and maternal and infant health. 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 organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards, program projects (P01), and center grants (P50). Applications from minority individuals and women are encouraged. MECHANISMS OF SUPPORT Applicants may use the research project grant (R01), program project (P01), center grants (P50), and FIRST (R29) award. Prospective applicants are encouraged to communicate with the NINDS program contact listed under INQUIRIES regarding the appropriate funding mechanism. RESEARCH OBJECTIVES Background It is estimated that of the 3,000 known genetic disorders, as many as one-third are primarily neurologic or have important neurologic involvement. Most of them have a low incidence, but collectively they represent an enormous burden on affected individuals, their families, and society. Many of these neurogenetic disorders manifest themselves early in life leading to either a premature death or to a lifelong disability with significant attendant psychological and economic hardships. Any attempt to group all the neurogenetic diseases of early life is somewhat arbitrary given that for many the underlying pathological mechanisms are incompletely understood. Examples of disorders of interest to the NINDS include: 1. Hereditary ataxias and related disorders such as Friedreich ataxia, ataxia telangiectasia, olivopontine cerebellar degeneration, Ramsay Hunt syndrome, abetalipoproteinemia, Machado-Joseph disease, and familial spastic paraparesis. 2. Movement disorders such as Juvenile Huntington disease, the dystonias including blepharospasm and spasmodic torticolis, tremor, myoclonus, and Hallervorden-Spatz disease. 3. Phakomatoses, or neurocutaneous syndromes such as neurofibromatosis, tuberous sclerosis, Sturge-Weber, and Von Hippel-Landau disease. 4. Mitochondrial encephalomyopathies such as the MELAS syndrome, Kearns-Sayre, and Leigh disease. 5. Hereditary disorders of nerve and muscle such as infantile spinal muscular atrophy, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathies, genetic myasthenic syndromes, metabolic myopathies, muscular dystrophies, and myotonias. In addition to diseases that have their major effects on the nervous system, many inborn errors of metabolism affect several systems, including the nervous system. The NINDS is interested in supporting research in the metabolic diseases where the research proposed is directed at the nervous system manifestations of the disorder. Examples of these metabolic diseases include, but are not limited to: 1. Disorders of lipid metabolism such as Gaucher disease, Niemann-Pick disease, the neuronal ceroid lipofuscinoses including Batten disease, the leukodystrophies, and the gangliosidoses including Tay-Sachs disease. 2. Disorders of carbohydrate metabolism such as galactosemia and hereditary fructose intolerance. 3. Glycogen storage diseases such as Von Gierke, Lafora disease, and Pompe disease. 4. Organic acidurias such as proprionic acidemia and methylmalonic acidemia. 5. Disorders of purine metabolism such as Lesch-Nyhan syndrome, and porphyria. 6. Disorders of amino acid metabolism and transport such as phenylketonuria, homocystinuria, maple syrup urine disease, urea cycle defects, Hartnup disease, and Lowe syndrome. 7. Disorders of mucopolysaccharide metabolism such as Hunter, Hurler, and Sanfilippo syndromes. 8. Disorders of metal metabolism such as Wilson disease and Menkes syndrome. There are numerous other neurological disorders that also result from genetic abnormalities such as the Laurence-Moon-Bardet-Biedl, Aicardi, Sjogren-Larsson, Prader-Willi and Angelman syndromes. In addition to those diseases that have a recognizable pattern of inheritance, there are many other neurological disorders that seem to have, in some cases, a familial basis. These may well represent neurogenetic disorders with multifactorial etiology. Such diseases can be as diverse as disorders of defective cellular migration (such as lissencephaly, heterotopias), neural tube defects, congenital hydrocephalus, myoclonic epilepsy, and narcolepsy. Research Goals and Scope Grant applications to study human neurogenetic disorders involving affected individuals and their family members are encouraged. Because the phenotypes of many neurogenetic disorders do not appear until childhood or early adolescence, the development of animal models is also important. Such models could make possible the detection of early biochemical changes, allow characterizations of the chemical pathology, and facilitate study of how genetic mutation disrupts the normal pathways of nervous system function. Areas of research interest include, but are not limited to, the following: A. Clinical Pathologic Correlations. Studies are needed to delineate the relationship of the clinical picture to pathological findings. Histopathological studies, including neurochemical studies of fresh tissue, which provide data for basic understanding of the relationship between pathophysiology and the evolution of clinical signs and symptoms, as well as the course of the disorder are encouraged. B. Genetics. Classical genetic studies have been used to establish the mode of inheritance for many of these disorders. This information will provide insight as to whether etiologic heterogeneity exists, and if sporadic cases are due to reduced penetrance or represent phenocopies. The most important contributions of genetic studies would be to establish the linkage relationships of the genes responsible for these disorders, and the identification of the defective gene and its normal biological role. State of the art methodologies for such studies should be used. C. Biochemistry. Studies should be directed at discovering the metabolic defect in each of these disorders and identifying its molecular basis. Successful biochemical studies will lead to an understanding of the pathogenic mechanisms and make possible the recognition of the heterozygote. Currently available advanced and sophisticated methodologies should be brought to bear on this important research. D. Neuroimaging. New neuroimaging technologies (PET, SPECT, MRI) can be applied to neurogenetic research problems and provide important clues about brain function under pathophysiological conditions and allow for correlation with the clinical disease state. E. Neuroepidemiology. There are some neurological diseases in which the genetic abnormality may not be the primary reason for the expression of the disorder. Epidemiological study of at risk families or clusters of cases might provide important clues of the interaction between genetic and non-genetic factors in producing the clinical symptomatology. 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 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 offices of sponsored research of most institutions eligible to receive Federal grants and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/594-7249. Applicants for program project grants should request a copy of the NINDS Guidelines: Program Project and Research Center Grants from the program staff listed under INQUIRIES. 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 applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST 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 provide the name of this Program Announcement (Neurogenetic Disorders of Infancy and Childhood) 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: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** For program projects or center grants, submit the original and three copies to the Division of Research Grants. An additional two copies of the program project or center grant application must be sent to Dr. Judy Small at the address listed under INQUIRIES to expedite the processing of these applications for multidisciplinary efforts. REVIEW CONSIDERATIONS Several other Institutes at the National Institutes of Health also have an interest in supporting areas of research covered by this PA. Applications will be assigned on the basis of established Public Health Service referral guidelines and some applications may receive dual assignments. In the case of R01 and R29 applications, they will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures and criteria. Program project applications will be reviewed by initial review groups organized by the Institute to which the application is assigned. Following scientific-technical review, the applications will receive a second-level review by the Institute's 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: o quality of the proposed projects as determined by peer review, o availability of funds, and 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. Questions concerning scientific aspects of this Program Announcement and application procedures may be addressed to: Dr. Judy A. Small Division of Convulsive, Developmental, and Neuromuscular Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 8C04 Bethesda, MD 20892 Telephone: (301) 496-5821 FAX: (301) 402-0887 Questions concerning fiscal aspects of this Program Announcement may be addressed to: Mr. King P. Bond, Jr. 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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