1985 |
Forster, Hubert V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanism(S) of Hypernea Elicited by Co2 Inhalation @ Medical College of Wisconsin
Our major objective is to enhance understanding of the ventilatory control system. A second objective is to enhance understanding of the general physiologic effects of chronic CO2 inhalation. To achieve these objectives, four specific studies will be completed on awake ponies. We will first determine the effect of sectioning the hilar branches of the vagus nerve (termed lung denervation, LD) on the Hering Breuer inflation reflex, and on ventilation (VE), respiratory timing, blood gases and pHa during eupnea, and during conditions of acute CO2 inhalation, acute hypoxia, muscular exercise and thermal stress. These studies, on 6 ponies before and 3 weeks after LD, should provide insight into the role of slowly adapting pulmonary stretch receptors in regulation of ventilation. The second study will be on 4-6 normal, 4-6 LD, and 4-6 carotid body denervated (CBD) ponies before, during and after 3 weeks of chronic exposure to 2 percent CO2. What is the relationship during chronic CO2 inhalation between VE and known or postulated VE stimulants (plasma and cerebrospinal fluid (CSF), PCO2, H+, morepinephrine, and NH3)? What is the effect of LD and CBD on the hyperpnea during chronic CO2 inhalation (which in other species is sustained in spite of normalization of [H+] in plasma and CSF)? What is the effect of chronic CO2 inhalation on body temperature, metabolic rate, systemic and pulmonary vascular pressures, and renal and endocrine functions that regulate blood volume and its composition? In the third study, we will determine the effect of L2 spinal lesions on the VE and cardiovascular responses to muscular exercise. Six ponies will exercise on a treadmill (4 legs, hindlegs only, and forelegs only) before and 2 weeks after partial lesioning of the dorsal lateral sulcus (DLS) and dorsal lateral funiculus (DLF). And finally we wish to determine whether occlusion, redundancy and/or plasticity exist within the ventilatory control system. If LD or spinal lesions alter ventilatory responses, then will these responses gradually return toward normal (as occurs following CBD)? Is the effect of a specific neurotomy (CBD, LD, DLS and DLF lesions) altered by a prior or a simultaneous lesion of a second receptor or neural pathway? In addition to providing insight into basic regulatory mechanisms, these studies are important because of the insight they should provide relative to patient care in situations where individual or multiple components of the ventilatory control system are chronically compromised.
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1986 — 2004 |
Forster, Hubert V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Control of Breathing During Physiologic Conditions @ Medical College of Wisconsin
DESCRIPTION (Adapted from the applicant's abstract): The retrotrapezoid nucleus (RTN) and the pre-Boetzinger complex/intermediate ventral respiratory group (pre-Boetc/iVRG) near the ventrolateral medullary (VLM) surface are critical for breathing in anesthetized and reduced preparations. However, studies on goats during surface VLM cooling suggest important differences between anesthetized, awake and NREM sleep states in VLM control of breathing and respiratory pump (RP) and upper airway (UAW) muscle activity. Surface cooling cannot, though, identify cell groups nor elucidate their physiologic functions. The objective of this proposal is to study the role of the RTN and pre-Boetc/iVRG in control of breathing and RP/UAW muscles during awake and NREM sleep states. To create reversible neuronal dysfunction in goats, excitatory amino acid receptor antagonists will be injected into the RTN or pre-Boetc/iVRG through guide tubes chronically implanted bilaterally. Hypotheses include: 1) under anesthesia, injections of non-selective receptor antagonists into the RTN or pre-Boetc/iVRG will cause apnea; 2) in awake and NREM sleep states, antagonist injection into the RTN and pre-Boetc will only slightly alter the timing and drive of breathing during eupnea; 3) antagonist injections into both cell groups will attenuate ventilatory responses to carbon dioxide, oxygen and exercise; 4) antagonist injections into the RTN will reduce the activity of UAW muscles more than RP muscles. Validation of these hypotheses would indicate that during awake and NREM sleep states, respiratory rhythm is not critically dependent on the RTN or pre-Boetc, although each site is important in the control of breathing and RP/UAW muscles. The data will enhance understanding of diseases such as brain-stem stroke, congenital central alveolar hypoventilation, and central and obstructive sleep apnea.
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1996 — 2004 |
Forster, Hubert V |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Integrated Physiology Training--Molecule to Organism @ Medical College of Wisconsin
During the last ten years, training in Physiology departments in this country has undergone a transformation which precludes students from obtaining research training which spans the discipline from the whole animal to the cellular and molecular level. An exception is the Physiology Department of the Medical College of Wisconsin (MCW), which offers research training that emphasizes integration of knowledge at all these levels as well as development of an appreciation for the relationship of this knowledge to disease processes. This proposed program will continue to provide training in Cellular, Molecular, and whole Animal PhysIology. Trainees will be recruited nationally and will be selected on the basis of academic credentials, previous research experience, and commitment to a career in research and teaching. During a period of approximately five years, trainees will complete required and elective courses and a research project which includes use of the techniques of molecular biology, biochemistry, isolated tissues, and whole animal investigation. Emphasis will be placed on interpretation of the relationship of data obtained from subcellular systems to the normal and abnormal physiology of the whole animal. Research will be in the areas of hypertension, stroke, and pulmonary disease, and will be designed to provide trained biomedical scientists in those areas of need, each of which has been targeted by NIH. Research training will be conducted under the supervision of the primary faculty of the training program (faculty of the Department of Physiology) in conjunction with secondary faculty who have been selected for their special expertise in an aspect of molecular biology, biochemistry, gene expression, cardiovascular, or pulmonary research using the whole animal. The secondary faculty are members of Departments of Anesthesiology, Biochemistry, Cellular Biology and Anatomy, Medicine, Microbiology, Pathology, and Pharmacology & Toxicology; the adjacent location of their research laboratories promotes active interaction between students and faculty in the Department of Physiology. Primary faculty will serve as dissertation advisors; secondary faculty will serve on dissertation committees and will function as research consultants. All trainees will be full-time Ph.D. candidates in the MCW Graduate School. Trainee progress in developing critical, integrative thought and in acquiring the skills required to successfully contribute to continuing studies on prevention and control of cardiovascular and pulmonary disease will be monitored at regular intervals. A plan is described for evaluation the success of the program in meeting its training objectives.
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2001 — 2005 |
Forster, Hubert V |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Integrated Physiology Training-- Molecule to Organism @ Medical College of Wisconsin |
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2007 — 2010 |
Forster, Hubert V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Control of Breathing During Physiological Conditions @ Medical College of Wisconsin
[unreadable] DESCRIPTION (provided by applicant): Recently, the debate regarding respiratory rhythm and pattern generation has changed dramatically with the emergence of novel hypotheses that rhythm and pattern are generated by a state- and condition-dependent hybrid-network of brainstem respiratory neurons, or by dual medullary oscillators. One view of the latter is that a pre-Botzinger Complex (pre-BotzC) inspiratory and a para-facial (pFRG) expiratory rhythm generator are reciprocally coupled to mediate the alternate phases of the respiratory cycle with the pre-BotzC dominant during in vivo conditions. A second view is that pre-inspiratory neurons in the pFRG determine the respiratory rhythm. These novel hypotheses are based on data from neonatal and juvenile rats in in vitro or anesthetized preparations, and there is only conflicting indirect evidence as to whether there is a functional pFRG rhythm generator in adult mammals. Our in vivo physiologic preparation is ideally suited to address these controversies regarding intact network behavior. Accordingly, in our proposed studies, microtubules will be chronically implanted bilaterally into the pre-BotzC or pFRG of adult goats to inject agents while awake or asleep that will reversibly or irreversibly alter neuronal activity. Five hypotheses will be tested: 1) During awake and NREM sleep states, neurons within the pre- BotzC inhibit an expiratory muscle rhythm generator at another brainstem site, 2) During awake and NREM sleep states, an intact pFRG is required for activation of abdominal expiratory pump muscles and airway constrictor muscles, 3) After destruction of a medullary site critical for generation of the eupneic respiratory rhythm and pattern, there is plasticity within the respiratory control network to restore the eupneic rhythm and pattern, 4) Plasticity after chronic unilateral or bilateral destruction of the pre-BotzC or the pFRG is associated with a serotonin and neurotrophin mediated increased synaptic efficacy and increased neuronal activity at unlesioned rhythmogenic sites, and 5) Respiratory rhythm and pattern generating mechanisms are state and condition dependent. We will show that in adult mammals during awake room air conditions, both the pre-BotzC and the pFRG are required for the eupneic respiratory rhythm and the eupneic activation pattern of the pump and airway respiratory muscles. However the role of each site is not hardwired as lesions at either site will not uniformly alter rhythm and pattern over different conditions and states, and plasticity after lesioning one site will enable the other site to alone generate the eupneic rhythm and pattern. Our studies are particularly important because they directly pertain to conditions humans experience in their everyday lives, and because major respiratory diseases such as sleep apnea, sudden infant death, congenital central alveolar hypoventilation, and neurodegenerative disorders all are characterized by state related disorders of breathing. [unreadable] [unreadable] [unreadable]
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2008 — 2020 |
Forster, Hubert V |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Integrated Physiology Training: Molecule to Organism @ Medical College of Wisconsin
DESCRIPTION (provided by applicant): Over the last twenty years, training in Physiology departments throughout the country has undergone a transformation that precludes students from a thorough understanding that spans the breadth of the discipline from the whole animal to the cellular and molecular level. An exception is the Physiology Department of the Medical College of Wisconsin (MCW), that offers research training emphasizing integration of knowledge at all of these levels with development of an appreciation for the relationship of this knowledge to disease processes. With the current proposal, we will continue providing this exceptional training in cellular, molecular, and whole animal Physiology for six NIH-supported trainees each year. A unique aspect of the proposed training is the mentoring program, which includes basic scientists from a variety of traditional areas as well as clinician scientists. Graduate students wll be recruited nationally and will be selected on the basis of undergraduate academic credentials, previous research experience, and commitment to a career in research. Students must complete the first year of graduate school before they will be considered for NIH training support. Selection of trainees will be based primarily on performance in course work and in the research laboratory during the first year of graduate school. Trainees are full-time Ph.D. candidates in the MCW Graduate School of Biomedical Sciences. Trainees will complete required and elective courses and a research project that includes use of the techniques of molecular biology, isolated tissues, and whole animal or clinical investigation. The major objective is to provide trainees with a broad foundation in interdisciplinary basic science and translational research. The trainee will develop the critical thinking, integrative reasoning, and technical skills required to create and participate in evolving research careers related to prevention and control of hypertension, stroke, and respiratory diseases. An innovative feature of the training is the emphasis on addressing the national need to train for the integrated-systems future of biomedical research in the post- genome era. Research training is under the direct supervision of Physiology faculty along with co-mentors from other basic science and clinical departments. Trainees and their mentors will undergo continuous evaluation of progress through a series of formal and informal meetings with the program director and the graduate committee. (End of Abstract)
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1 |
2013 — 2016 |
Forster, Hubert V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Interdependence Among Neuromodulators of Ventilatory Control @ Medical College of Wisconsin
DESCRIPTION (provided by applicant): Neurons within the respiratory network initiate and coordinate respiratory pump and airway muscle activation to adjust the level of pulmonary ventilation ( I) to maintain blood gas homeostasis. Chemoreceptors provide major excitatory drives to breathe (19, 22, 31, 65, 82), but it is the overall balance of excitatory and inhibitory neuromodulators that ultimately determine respiratory network excitability (15, 16, 28, 92). The contribution of endogenous neuromodulators to eupneic I while awake or asleep has not been determined, but in vitro evidence suggests that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators (16). The overall goal of our proposal is to test this hypothesis of neuromodulatory interdependence and test whether inadequate interdependence contributes to sleep disordered breathing (SDB) and/or opiate overdose-induced respiratory depression. In adult goats, microtubules will be chronically implanted for insertion into the preB¿tzinger Complex (preB¿tC) or hypoglossal motor nucleus (HMN) of probes for dialysis in mock cerebral spinal fluid (mCSF) of antagonists or agonist of excitatory or inhibitory neuromodulators during awake and asleep states. We will measure I, diaphragm and genioglossus (GG) muscle activity, and neurochemicals in effluent dialyzed mCSF. Specific Aim 1 determines whether there is interdependence among multiple excitatory neuromodulators within the preB¿tC. We hypothesize that: a) antagonists of muscarinic cholinergic, serotonin (5-HT2A), or neurokinin-1 receptors individually will have little or no effet on eupneic I and GG muscle activity but in combination will attenuate I and GG activity particularly during sleep and lead to SDB, b) antagonists of excitatory neuromodulatory inputs to the preB¿tC will produce compensatory changes in other neuromodulators at the site of antagonist dialysis. Specific Aim 2 determines whether there is interdependence within the preB¿tC between excitatory neuromodulators and the inhibitory neuromodulatory effects of ¿-opioid receptor activation. We hypothesize that: a) preB¿tC ¿-opioid receptor activation will depress I and GG activity while awake and to a greater extent during sleep, b) preB¿tC ¿-opioid receptor activation will not alter effluent neurochemical content and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors. Specific Aim 3 determines whether there is interdependence among neuromodulators of the HMN. We hypothesize that: a) unilateral dialysis of a ¿- opioid agonist within the HMN will decrease I and GG activity which during NREM and REM sleep will lead to SDB, b) there will be no compensatory changes in any of the measured local neurochemicals in the effluent mCSF during opioid dialysis, and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors.
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