Neil Stanley Cherniack, MD - US grants

The underlying premise is that respiration can only be understood in the context of the interplay among controlled elements, the controller, and the nonrespiratory influences on both the controller and the controlled element, seen as an integrated system. Each element of the system contributes to the modulation of ventilation in the normal resting state, but the relative importance of these components may change under conditions of environmental stress or disease. This program consist of seven projects. Project 1 deals with the central factors that coordinate respiratory skeletal muscle function (Project 1A) and the medullary mechanisms concerned with integration and coordination of respiratory and cardiovascular responses (Project 1B). Project 2 evaluates the behavioral aspects of respiratory control and the relationship between the conscious perceptions of respiratory sensation to dyspnea and respiratory motor responses. Project 3 assesses the neuromuscular regulation of breathing in infants with emphasis on the function of upper airway muscles. Project 4 investigates breathing during sleep in adults. The focus of Project 4A is the functional responses of the upper airway muscles and their interrelationship with the geometry and dynamic mechanical properties of the upper airway; while Project 4B studies the mechanisms that produce and terminate recurrent apneas and periodic breathing. The emphasis of Project 5 is on the regulation of respiratory muscle blood flow and its role in adaptation to stress. Project 6 deals with the neural control of the respiratory muscles and how it is related to the cellular mechanisms that affect airway responses. The central regulation of airway smooth muscle activity is the focus of Project 6A; thermal factors acting reflexly and directly on the airway are studied in Project 6B; while Project 6C examines the effect of the intrinsic cellular characteristics of smooth muscle on airway responsivity. Project 7 explores the mechanisms which control the reactions of the lung to injury and their possible implications in the control of breathing. Basic data will be obtained on the organization and operation of the respiratory controller and its interaction with other control systems. Additionally, the studies have been designed to identify mechanisms and risk factors at the system and cellular level for respiratory failure which will be useful in devising and evaluating therapeutic interventions.

A number of neuroactive substances have been implicated in the regulation of breathing. Two classes of putative neurotransmitters, the tachykinins (particularly substance P and neurokinin A) and catecholamines (especially dopamine) seem to be critically involved at several levels of the neuraxis (the carotid body, the petrosal ganglion, and the medulla) in mediating the hypoxic response. At the carotid body, for instance, substance P (SP) and neurokinin A (NKA) have excitatory effects while dopamine (DA) usually inhibits. Although a similar kind of regulation may occur at other sites, the precise interaction depends on the immediate biochemical environment (including the presence of other transmitters) and local anatomic connections. In addition, the interplay among SP, NKA and DA may vary as hypoxic stimulation is maintained. The proposed research uses cross-disciplinary approaches to define how tachykinins and dopamine participate in shaping the respiratory increase caused by hypoxia. This study has as its goals: (a) To determine the interplay of tachykinins and dopaminergic elements in the carotid body in modulating the afferent activity of single fibers and in causing the release of tachykinins and dopamine. Both in vivo and in vitro preparations of the cat will be used. (b) To define the expression and regulation of peptidergic and dopaminergic phenotypic traits in chemoreceptor afferent neurons. Combined retrograde tracing and immunochemistry will be used to delineate precisely the localization of tachykinins and peptides within carotid body afferents and to define the relationship of peptidergic and dopaminergic expression in vivo. In addition, cultured rat petrosal ganglion neurons will be used as a model system to elucidate the regulation and plasticity of peptidergic and dopaminergic traits of carotid body afferents in vitro. (c) To examine in cats the role of tachykinins and dopamine in the processing of chemoreceptor signals in the nucleus tractus solitarius and nucleus paragigantocellularis using anatomic and electrophysiologic techniques, as well as by measuring the release of tachykinins and dopamine. By defining transmitter interaction in these chemoreceptor pathways the proposed research may shed light on fundamental principles of biochemical organization, applicable to the nervous system as a whole.

biomedical equipment resource; biomedical equipment purchase;

biomedical equipment purchase;

The purpose of this animal resource improvement project is to provide the planned expansions to the animal housing area and the core surgical facility of the CWRU Animal Resource Center (ARC) with major items of basic equipment essential to ensure the high level of animal care and support appropriate to the caliber of the research programs using these facilities while meeting or exceeding all PHS, USDA and AAALAC standards. In anticipation of a dramatic increase in the demand for sophisticated animal surgical facilities arising from major research programs currently under way or planned in conjunction with the construction of a new Biomedical Research Building to house 150 active CWRU faculty researchers (and involving cardiac catheterization in addition to heart, lung and liver transplants), this project seeks financial assistance in obtaining several basic items of operating room equipment for the expanded ARC core surgical facility. These include, operating tables, gas anesthesia machines with monitoring capabilities and animal CCU units. The institution's immediate goal is to obtain full AAALAC accreditation for all its animal facilities and animal care program and to complete its housing expansion and bring it into full operation as soon as possible to relieve the present animal housing shortage at CWRU. The School is firmly committed to the goal of having the new extensions to its animal facilities meet the highest possible standards for housing and for animal survival surgery. The long-term goals of the institution are simply to be able to house (in facilities of uncompromising quality) all species of laboratory animals (in the numbers required by investigators) that are essential to the research programs of its faculty and to provide a first rate core facility for survival (and acute) surgery that will significantly minimize the loss of animal life following the complex surgical procedures dictated by the demanding goals of the research programs.

The present application proposes to create a university based GCRC at Case Western Reserve University School of Medicine (CWRU). A satellite center at MetroHealth Medical Center is to be added to the long established unit at University Hospitals of Cleveland, and new outpatient activities in Pediatrics are to be supported in the Biomedical Research Building on the CWRU campus. The combined GCRC serves a wide range of research protocols for 58 investigators from 10 departments and 4 institutions. The major areas of research are the following: 1. Pathogenesis of airway responses in normal subjects and those with pulmonary diseases. 2. Carbohydrate and lipid metabolism in pregnancy 4. Sensor and instrument development for infant monitoring 5. Sleep apnea and circadian metabolic function 6. Clinical development of new therapeutics for colon cancer. 7. Traumatic brain injury in children 8. Moderation of central nervous system neurotransmitters in patients with psychiatric illness 9. Functional electronic stimulation of patients with neuro-musculo-skeletal dysfunctions 10. Immune homostasis and clinical treatment trials in AIDS 11. Psychological and development effects of environmental toxins on infants and children 12. Exercise physiology in health and disease in women and men

health science research support; medical education;

biomedical equipment purchase;