Full Text HD-94-011 DIAGNOSTIC METHODS TO ASSESS NEUROLOGIC INTEGRITY IN FETUS/NEONATE NIH GUIDE, Volume 23, Number 5, February 4, 1994 RFA: HD-94-011 P.T. 34 Keywords: Neurophysiology Diagnosis, Medical Fetus 0775013 National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Application Receipt Date: April 29, 1994 PURPOSE The objective of the RFA is to stimulate research on the development of effective technologies to assess the integrity and function of the developing brain in the human fetus and newborns. The long-term goal of this research is the identification of newborns with brain dysfunction due to early, repetitive or chronic intrauterine central nervous system (CNS) influences/insults, which may result in Sudden Infant Death Syndrome (SIDS) and developmental disabilities including cerebral palsy. Postnatally acquired and acute perinatal deficits are not within the scope of this RFA. The National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS) invite applications for studies in animals and/or humans that (1) elucidate the physiological parameters that would serve as reliable markers of central nervous system integrity/pathology; and (2) explore the development of technologies/clinical tools that might identify infants who have, or are at risk for, abnormal neurologic development or sudden death from prenatal insults. 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 priority areas. This Request for Applications (RFA), Assessment of the Nervous System in the Fetus and Newborn, is related to the priority area of maternal and infant health. 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 domestic and foreign 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 not eligible for the First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01) and FIRST Award (R29). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for R01 applications submitted in response to the present RFA may not exceed four years. R29 awards must be for five years. The earliest anticipated award date is September 30, 1994. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The estimated direct costs available for the first year of support for the entire program is $800,000 from the NICHD and $600,000 from NINDS. The anticipated number of new awards supported is four by NICHD and three by NINDS. RESEARCH OBJECTIVES Background Identification of infants at risk for abnormal neurologic development is a daunting clinical problem. It is increasingly clear that acute perinatal "asphyxia" accounts for a minor proportion of infants with abnormal neurologic outcome. Many more infants appear normal at birth but seem to have sustained as-yet poorly understood fetal insults. Although there is an imprecise understanding of the relationship between fetal insults and cellular events, there is general agreement that a hypothetical sequence of cellular events may occur by which hypoxia or ischemia may become cytotoxic. Work in animal models is clarifying the mechanisms operative in hypoxic-ischemic neuronal damage and has identified a number of potentially therapeutic interventions. An insult may cause immediate or delayed neuronal death or injury. A number of factors, including infectious agents, drugs, immune status, neuroendocrine status, etc., appear capable of influencing the developing brain's maldevelopment and vulnerability, and response to injury. The nature, degree, length, frequency, and reversibility of these influences, as well as genetic vulnerability of the fetus may determine the relative importance of the mechanisms and the location and severity of the deficits. The purpose of this solicitation is to develop methods to identify clinical parameters that may be used to define the fetus or newborn infant at risk for abnormal nervous system functioning as a result of fetal insult or maldevelopment. These parameters could include fetal markers in all three trimesters, and/or clinical parameters from the neonatal period. Manifestations of abnormal nervous system development include autonomic and state dysfunction that may lead to SIDS, sensory dysfunction, cerebral palsy or later cognitive disability. The ultimate goal is to define clinically useful parameters to identify the fetus or neonate who would benefit from the application of preventative and therapeutic interventions within an appropriate window of opportunity. Development of tools to evaluate the effects of CNS insults in order to enable direct investigation of cerebral cellular events in the human fetus and to relate cellular events to clinically observable signs is an important research priority. The methods must address quantitation of severity of exposure, vulnerability of the fetus, and the fetal response to the exposure. Such tools would improve our ability to diagnose fetuses and neonates who have and may continue to sustain brain injury in utero. Understanding of the temporal and pathophysiologic processes would allow identification of appropriate candidates for neuroprotective or neuronal rescue strategies and would facilitate development of preventive strategies. Scientific evidence supports the theory that some and possibly most SIDS infants are born vulnerable to sudden death in infancy due to chronic insults in utero. Detailed pathologic studies of the central nervous system of SIDS infants reveal abnormalities in regions that control respiratory organs, arousal from sleep, and the activation and control of cardiac function and breathing during sleep. The nature of the altered morphologies, i.e., abundance of dendritic spines and hypomyelination, suggest that the maturation of these regions is impaired in utero and early postnatal life. Recordings of heart rate and respiration of SIDS infants within the first weeks of life show that the variation of their heart rate in response to physiologic stimuli, such as breathing and blood pressure changes, or in adaptation to behavioral state (sleep/waking) is limited. These findings also suggest central autonomic nervous system immaturity or developmental disease. In addition, infants shown to be at risk from epidemiologic studies, such as infants experiencing an apparent life-threatening event (ALTE), premature infants, or a sibling of a SIDS infant, have been shown to have abnormal state dependent autonomic responses to stimuli such as hypoxia, hypercarbia, and temperature. The physiologic deficits observed in recordings of infants who later die or are at epidemiologic risk do not have the specificity to be used as screening tools. It would be a major step forward for clinicians and the research community if screening tools could be developed that would define abnormal neurologic development and/or intrauterine neurologic insult in the fetus and/or neonate that was associated with a significant risk of dying later in infancy, suddenly, and unexpectedly. Other The types of research approaches being sought by this RFA include, but are not restricted to: 1. Studies in animals that model early, recurrent, and/or chronic central nervous system influences/insults in utero and include assessments of central nervous system integrity in the fetus and neonate. Animal models must demonstrate relevance to the human fetus and neonate. The models should link severity of outcome with the nature of the insult (e.g., type, timing, duration, location). Examples of insults of interest include but are not limited to: hypoxia, hypoglycemia, hypovolemia, infectious agents, and exposure to substances of abuse. 2. Studies in human fetal and neonatal subpopulations suspected of being exposed to recurrent and/or chronic insults in utero that assess central nervous system integrity and link assessment with outcome. 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 are 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 must 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 (rev. 9/91) 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 Alaskan 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 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 application will be returned. 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 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 The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/710-0267; and from the program staff listed under INQUIRIES. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03 Bethesda, MD 20892 Applications must be received by April 29, 1994. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the Division of Scientific Review, National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS). Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NICHD and NINDS staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. The review criteria to be used are identified below. The NIH will administratively withdraw from competition those applications judged to be noncompetitive , and notify the applicant and institutional business official. Those applications judged to competitive will undergo further scientific merit review. The second level of review will be provided by the National Advisory Child Health and Human Development and National Advisory Neurological Disorders and Stroke Councils. Review criteria for this RFA are generally the same as those for unsolicited research grant applications. o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The earliest anticipated date of award is September 30,1994. Responsiveness to the RFA, scientific merit, and technical proficiency, as described in the application, will be predominant criteria for determining funding. Assignment For the purposes of this RFA: Applications relevant to Sudden Infant Death Syndrome will have primary assignment to the National Institute of Child Health and Human Development. Applications to further delineate the pathogenesis of fetal brain injury will have primary assignment for the purposes of this RFA to the National Institute of Neurologic Disorders and Stroke. Applications regarding the development of diagnostics to identify infants who could benefit from neonatal therapeutic strategies to prevent initiation or progression to brain injury will have primary assignment to either the National Institute of Child Health and Human Development or the National Institute of Neurological Disorders and Stroke. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Marian Willinger, Ph.D. or Linda Wright, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03 Bethesda, MD 20892 Telephone: (301) 496-5575 Giovanna Spinella, M.D. Division of Convulsive, Developmental and Neuromuscular Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 8C-10 Bethesda, MD 20892 Telephone: (301) 496-5821 Direct inquiries regarding fiscal matters to: Mr. Douglas Shawver Office of Grants and Contracts National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 Bethesda, MD 20892 Telephone: (301) 496-1303 Mr. King P. Bond Jr. Grants Management Branch National Institute of Neurological Disorders and Stroke Federal Building, Room 10004 Bethesda, MD 20892 Telephone: (301) 496-9231 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.365 (Research for Mothers and Children), and No. 93.853, Clinical Research Related to Neurological Disorders and 93.854, Biological Basic 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- 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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