Michael M. Myers - US grants

The experiments in this proposal are designed to give information that will help identify, early in life, individuals that are genetically predisposed to develop hypertension as adults. The first part of our strategy is to study psychological, biochemical and behavioral characteristics of a population of rats known to have a broad distribution of adult blood pressures, namely the F2 segregate population derived from spontaneously hypertensive rats (SHR). A second aspect of our program will be to first screen and then mate, according to rank ordering of blood pressures, rhesus monkeys from our primate breeding program. In one set of studies we will repeatedly measure a number of relevant parameters in a group of F2 rats starting during the preweaning period and continuing until the animals are adults. In these longitudinal studies we will measure: a) tail-cuff blood pressure and heart rate; b) respiratory sinus arrhythmia and other periodicities, that contribute to heart rate variability; c) heart rate and behavioral responses associated with exposure to a novel environment; and d) heart rate and behavioral responses following exposure to discrete auditory stimuli. These experiments will test the hypothesis that blood pressures among the F2s will maintain their rank order through development, and that certain, relatively non-invasive, measures will serve as early life markers for the development of adult hypertension. In another series of studies we will use groups of F2s of various ages. In these more invasive experiments the variables recorded will be: a) direct arterial (carotid) blood pressure; b) heart rate and heart rate variability; c) baseline and post-hemorrhage plasma levels of catecholamines, renin, angiotensin, vasopressin, and early electrolytes. These experimentals will allow us to test the hypothesis that there are early life biochemical anticedents of adult hypertension. Finally, we will study blood pressure development in a population of rhesus monkeys. There are three facets to these experiments: a) We will survey the blood pressures of all proven breeders and their offspring; b) We will selectively mate animals from this population in an attempt to create offspring with a broad distribution of blood pressures; c) We will determine whether the rank-order of blood pressures within the colony, and other measures suggested by our rat studies, will be maintained through development and hence serve to predict later life blood pressures in primates.

computer program /software

DESCRIPTION (provided by applicant): The proposed studies provide new knowledge for understanding how events early in life shape physiology, behavior, and susceptibility to disease later in life. They focus on variation in nutrient availability in the perinatal period. The long-term health related objectives of the work are to improve early identification of individuals at risk for adult disease, to discover new prevention strategies, and to identify epigenetic alterations that account for the persistence of the effects of early experiences. Both animal models and human infants are studied. Assessments include measures of physiological, biochemical and behavioral characteristics of infants in both species in the first few days after birth. Indices derived from animal studies will be incorporated into human studies, and the underpinnings of correlative findings from human studies will be pursued in animal models. The presupposition for the work is that individuals, undergrown during gestation, express adaptations that can be seen as changes in autonomic nervous system (ANS) development, cardiovascular (CV) regulation, and feeding behavior. Aim 1. To determine if human infants with low birth weights express differences in CV and behavioral responses to feeding, differences in heart rate and blood pressure responses to postural challenge, and differences in physiologic and behavioral responses to changes in taste and/or formula composition. Aim 2. To determine, in rats, the effects of reduced food availability during gestation on physiologic and behavioral characteristics during the preweaning period. Key measurements will include assessments of Newborn feeding behaviors and food preferences and CV and responses to food and feeding. Aim 3. To determine, in rats, how variations in nutrient availability after birth alter the effects of gestational malnutrition. Does experimental manipulation of food intake during the postnatal period reprogram the effects of fetal undergrowth and, if so, is there a critical period for this intervention? Aim 4. To determine, in rats, if there are changes in patterns of DNA methylation in kidney, liver, hypothalamus, placenta, and blood samples obtained from animals reared under the conditions of Aims 2 and 3. If so, the DNA sequences with alterations in methylation will be identified and this information will guide methylation studies targeted to specific genes in the placenta and cord blood samples from humans.

DESCRIPTION (provided by applicant): This program has been training M.D. and Ph.D. investigators to pursue careers in the psychobiological sciences related to mental disorders for nearly two decades. Clinical researchers and those working in the laboratory on animal models in the basic sciences are united by a common interest in the interplay of psychological and biological processes as these contribute to increased understanding of clinical disease. We emphasize training in an analytic experimental approach to elucidate the processes and mechanisms underlying the development of abnormal neural functioning and behavior. Specific areas of research interests of the 20 sponsoring faculty include: developmental psychobiology, chronobiology, perinatal physiology and behavior, psychosexual differentiation, anxiety disorders, brain imaging, psychopharmacology of pain systems, attachment and separation, epidemiology of psychiatric disorders, behavioral medicine, and genetic models of abnormal brain function. The research ideas and career goals of the trainee candidates are carefully matched with particular faculty member's expertise. Training focuses primarily on conducting research designed by the fellow with the guidance from faculty mentors. This hands-on research training is supplemented with 1) a weekly seminar in which the processes of research are intensively discussed with a core group of sponsoring faculty, and 2) personalized didactic study programs consisting of courses in statistics, lectures from medical school courses and a rich variety of seminars and rounds in psychiatry and psychobiology. The goal of the program is to promote the development of successful independent researchers. Toward this end, all fellows receive instruction in how to design and write competitive grant proposals. Funds are requested for six postdoctoral trainees. M.D.s are usually psychiatric residents with several years of postdoctoral experience. Ph.D.s usually begin their training with a year or two following completion of the graduate training. Selection is based on the applicants' potential for original and creative research; on their motivation and the perseverance required to complete 2-3 years of intensive research training. Creative selfstarters with their own ideas are sought and then matched with faculty mentors who can best guide this research.

DESCRIPTION (provided by applicant): This program has been training M.D. and Ph.D. investigators to pursue careers in mental health related research for over two decades. Clinical researchers and those working in the laboratory on animal models in the basic sciences are united by a common interest in the interplay of psychological and biological processes, especially during early development, as these contribute to increased understanding of clinical disease. We emphasize training in an analytic experimental approach to elucidate the processes and mechanisms underlying the development of abnormal neural functioning and behavior. Specific areas of research interests of the 24 sponsoring faculty include: developmental neuroscience, chronobiology, perinatal physiology and behavior, psychosexual differentiation, anxiety disorders, brain imaging, psychopharmacology of pain systems, attachment and separation, epidemiology of psychiatric disorders, behavioral medicine, and genetic models of abnormal brain function. Training focuses primarily on conducting research designed by the fellow with guidance from faculty mentors. This hands-on research training is supplemented with 1) a weekly seminar in which the processes of research are intensively discussed with a core group of sponsoring faculty, and 2) personalized didactic study programs consisting of courses in statistics, lectures from medical school courses and a rich variety of seminars and rounds in psychiatry and neuroscience. The goal of the program is to promote the development of successful independent researchers. Toward this end, all fellows receive instruction in how to design and write competitive grant proposals. Funds are requested for six postdoctoral trainees. M.D.s are usually psychiatric residents with several years of postdoctoral experience. Ph.D.s usually begin their training with a year or two following completion of graduate training. Selection is based on the applicant's potential for original and creative research, and on their motivation and perseverance required to complete 2-3 years of intensive research training. Creative self-starters with their own ideas are sought and then carefully matched with faculty mentors who can best guide this research.

DESCRIPTION (provided by applicant): The goal of the PASS Network is to determine the role of prenatal alcohol exposure in the risk for the sudden infant death syndrome (SIDS) and adverse outcomes of pregnancy, particularly stillbirth and fetal alcohol spectrum disorders (FASD), and in the potential inter-relationships between SIDS, stillbirth, and FASD. This application is in response to the Request for Application (RFA-HD-10-018) entitled "Role of Prenatal Alcohol Exposure in SIDS and Stillbirth". As requested, it proposes the completion of enrollment and follow-up of study participants and the performance of data analysis in Phase II of the PASS Network by the current five clinical, physiologic, biologic/pathologic, and data coordinating centers. The mission of the network is to conduct community-linked studies to investigate the role of prenatal alcohol exposure in the risk for SIDS, stillbirth and FAS, and to determine how these different outcomes are inter-related. The PASS Network is a collaborative effort comprised of two Comprehensive Clinical Sites (CCS) - Northern Plains Comprehensive Clinical Site (NPCCS) and Stellenbosch Comprehensive Clinical Site (SCCS), a Developmental Biology and Pathology Center (DBPC), a Physiology Assessment Center (PAC), and a centralized Data Coordinating and Analysis Center (DCAC) and program scientists and officers at the NICHD and NIAAA. This particular application pertains to the Physiology Assessment Center (PAC) of the PASS Network. The role of the PAC is to oversee the data collection infrastructure and analyze the physiological data from the 12,000 subjects tested at the PASS Network Clinical Sites. These early assessments will define physiological consequences of prenatal alcohol and other exposures prior to the development of adverse outcomes. The potential impact of this work is that, in combination with pathological, environmental and genetic findings, we will be better able to define the mechanisms that underlie vulnerability to stillbirth SIDS and FASD. The information gained will provide the potential for prospectively identifying fetuses and infants at greatest risk and the possibility for more precise targeting of early interventions. PUBLIC LEALTH RELEVANCE: The PASS Network will perform community-linked studies to determine the role of prenatal alcohol exposure in the risk for SIDS and adverse pregnancy outcomes, especially stillbirth and FASD. The study hopes to decrease fetal and infant death and improve child health in communities at high risk for prenatal maternal alcohol consumption.