1988 — 2007 |
Mifflin, Steven W. |
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. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Chemoreceptor Input to Non-Respiratory Cells in Nts @ University of Texas Hlth Sci Ctr San Ant
chemoreceptors; pulmonary respiration; neural transmission; cardiovascular system; solitary tract nucleus; carotid body; afferent nerve; respiratory gas; hypothalamus; neural information processing; spinal cord; electrostimulus; cats; decerebration; evoked potentials; electrophysiology;
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0.917 |
1995 — 2003 |
Mifflin, Steven W. |
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. |
Chemoreceptor Input to Nonrespiratory Cells in Nts @ University of Texas Hlth Sci Ctr San Ant
This proposal represents a continuing effort to identify the cellular mechanisms which underlie the integration of peripheral, cardio- respiratory afferent inputs within the central nervous system. I will continue to investigate the integration of arterial chemoreceptor (CR) afferent inputs within the nucleus tractus solitarius (NTS), the initial site of termination of CR afferent fibers within the central nervous system. During the previous funding period the synaptic basis of CR afferent integration within NTS was examined. This proposal will extend these observations and begin an examination of the pharmacological mechanisms which underlie CR afferent integration within the NTS. Specifically, the role of two neurotransmitter receptors which have been implicated as possible mediators of CR evoked excitation of NTS neurons will be examined. A large body of evidence suggests that both excitatory amino acid and tachykinin receptors within NTS play a role in chemoreflex regulation of the cardiovascular and respiratory systems. This proposal will use two complimentary approaches to investigate the possible role of excitatory amino acid and tachykinin receptors in the integration of CR inputs within NTS in anesthetized rats. Extracellular recording and iontophoretic techniques will be used to examine NTS neurons receiving mono- and/or poly-synaptic CR inputs and determine the effects of excitatory amino acid and tachykinin receptor agonists and antagonists on (1) spontaneous discharge, (2) carotid sinus nerve evoked discharge and (3) CR evoked discharge. Intracellular recording techniques will be used to further study the integration of CR afferent inputs within NTS by examining (1) membrane potential responses to a graded series of CR stimuli and (2) if the response to activation of CR inputs is altered (enhanced) during and following high frequency stimulation of the carotid sinus nerve. Intracellular recording techniques will be used in combination with immunohistochemical techniques to determine morphology, axonal projection, and the anatomical relationships between tachykinin (Substance P) immunoreactive elements and NTS neurons receiving CR inputs at both the light and electron microscopic level. The immunohistochemical studies will provide insights into the anatomical substrates of afferent integration within NTS, while the iontophoretic studies will provide insights into the functional significance of neuroactive substances previously implicated in cardio-respiratory regulation. These studies will extend our understanding of physiological and pharmacological mechanisms mediating the central integration of CR afferent inputs. Such information is critical if we are to fully understand mechanisms by which the central nervous system regulates blood pressure and respiration in normal (e.g., exercise, sleep) and pathophysiological conditions (e.g., hypertension, hypoxia and hemorrhage).
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0.917 |
1996 — 2004 |
Mifflin, Steven W. |
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. |
Gaba Mechanisms in Baroreceptor Integration in Nts @ University of Texas Hlth Sci Ctr San Ant
The overall goal of this proposal is to gain a better understanding of how the brain integrates the information it receives from the arterial baroreceptors. Such understanding provides insights into how the central nervous system regulates blood pressure and heart rate under normal and pathological situations. During the tenure of this award we have shown that the physiological and pharmacological mechanisms responsible for the integration of baroreceptor afferent inputs are altered in chronically hypertensive animals. The specific goal of this competitive renewal is to further define the nature, the time course and the functional significance of these alterations. To this end, experiments have been designed to test the general hypothesis that the central resetting of the arterial baroreflex observed in chronic renal wrap hypertension is mediated, at least in part, by inhibition of transmission within the NTS. Previous work during the tenure of this award has provided insights into specific alterations that occur in hypertension; therefore 4 specific aims are proposed to test hypotheses that arise from these studies. Specific Aim 1: Chronic hypertension is associated with increased GABAA mediated inhibition within the NTS. This inhibition is the result of an increase in the discharge of GABAergic neurons in the NTS. These GABAergic neurons inhibit other NTS neurons that integrate baroreceptor afferent inputs; therefore these changes contribute to a blunting of NTS neuronal responses and reflex resetting. Specific Aim 2: Chronic hypertension induces increased post-synaptic expression of GABAB receptors in NTS neurons receiving monosynaptic aortic nerve inputs. This increase in GABAB receptor function contributes to a blunting of NTS neuronal responses and reflex resetting in chronic hypertension. Specific Aim 3: Alterations in GABAA and GABAB mechanisms within the NTS of chronically hypertensive rats result from a tonically elevated level of peripheral afferent input from the arterial baroreceptors and cardiopulmonary mechanoreceptors. Specific Aim 4: In chronically hypertensive rats the number of NTS neurons active at the resting level of arterial pressure and the number of neurons activated in response to graded increases in pressure is increased compared to the number of neurons active and activated in normotensive rats. The level of baroreceptor afferent input to the NTS is increased in hypertension. It is hypothesized that during chronic hypertension alterations occur in the physiology and pharmacology of NTS neurons that result in enhanced inhibition and counteract the elevated afferent input. This normalizes NTS neuronal discharge and thereby reflex gain. These adaptations confer a baroreflex buffering capability that might otherwise be greatly reduced in hypertension. Therefore, understanding the mechanisms that induce and underlie these adaptations will be of great importance in our understanding of cardiovascular regulation in hypertension.
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0.917 |
2000 — 2003 |
Mifflin, Steven W. |
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. |
Cardiovascular Responses to Chronic Intermittent Hypoxia @ University of Texas Hlth Sci Ctr San Ant
Chronic intermittent hypoxia (CIH) is a widely used model for the repetitive bouts of hypoxemia that occur during sleep in sleep apnea patients. During such apneic periods, hypoxia activates chemoreceptors that evoke reflex increases in arterial pressure. In humans with sleep apnea and animals exposed to CIH the repetitive periods of hypoxia during sleep result in tonically increased arterial pressure during waking hours, likely the result of elevated levels of sympathetic nerve activity and an enhanced response to acute hypoxia. The goal of the present project is to investigate the central pathways and mechanisms that underlie this persistent increase in sympathetic nerve activity. It is hypothesized that CIH leads to alterations in ligand gated excitatory and/or inhibitory amino acid receptors in noradrenergic (A2) neurons in the nucleus of the solitary tract (NTS) so that their discharge is increased compared to before CIH. These neurons transmit this enhanced discharge to sympatho-excitatory neuron in the paraventricular nucleus (PVN) of the hypothalamus. PVN neurons receiving the catecholaminergic input include neurons that release corticotropin releasing factor (CRF) as a transmitter. The CRF releasing PVN neurons mediate, at least in part, the enhanced sympathetic discharge observed following CIH via projections to the RVLM and by stimulating corticosterone release. Both in vivo and in vitro approaches will be used and microinjection, electro-physiological and molecular studies are proposed to characterize the synaptic integration of chemoreceptor inputs and the molecular regulation of the neurotransmitter receptors that mediate these integrative processes. The specific aims are designed to assess: 1) The integration of arterial chemoreceptor inputs within the NTS following CIH; 2) The integration of A2, noradrenergic inputs within the PVN following CIH; and 3) The functional activation of the CRF system within the PVN following CIH.
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0.917 |
2007 — 2008 |
Mifflin, Steven W. |
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. |
Alterations in Chemoafferent Integration Induced by Chronic Intermittent Hypoxia @ University of Texas Hlth Sci Ctr San Ant
[unreadable] DESCRIPTION (provided by applicant): Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during sleep apnea. CIH in animals has been shown to result in an increased blood pressure as seen in human sleep apnea patients and this hypertension is dependent upon the sympathetic nervous system (SNS) and angiotensin (Angll). Current explanations for CIH-induced hypertension include arterial chemoreceptor activation providing a driving force for a persistent increase in sympathetic nerve discharge. The nucleus of the solitary tract (NTS) is the primary CNS site of termination of arterial chemoreceptor afferent fibers. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors by CIH increases the discharge of and the responsiveness of neurons in the NTS that regulate sympathetic and HPA axis function. The adrenal steroid corticosterone (CORT) has been shown to be increased following acute exposures to hypoxia. CORT has been shown to enhance the pressor effect of centrally administered Angll and Angll within the NTS facilitates synaptic and chemoreflex responses. It is hypothesized that enhanced Angll mediated responses (increased calcium influx) result in enhanced responses to the excitatory transmitter AMPA. As a result, the sensitivity of NTS neurons to arterial chemoreceptor inputs is enhanced which contributes to the elevations in blood pressure, sympathetic nerve discharge and sympathetic reactivity observed after CIH. It is hypothesized that catecholaminergic (A2) and glutamatergic neurons in the caudal NTS are the primary sites where these alterations occur. Specific Aim 1: The first goal is to characterize how NTS neurons respond and adapt during exposure to CIH and the role of hypoxia in mediating/modulating responses to chemoreceptor afferent inputs. Specific Aim 2: The second goal is to determine the role of the glucocorticoid Type II receptor as a mediator of these adaptive changes in NTS neurons. Specific Aim 3: The third goal is to determine the role of angiotensin in the alterations in NTS neurons induced by CIH. The results of these studies will provide new insights into the mechanisms whereby CIH leads to elevated blood pressure, sympathetic nerve discharge and sympathetic reactivity. These factors mediate much of the pathology associated with sleep apnea including hypertension, increased risk of adverse cardiovascular events and insulin resistance. [unreadable] [unreadable] [unreadable]
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0.917 |
2008 — 2009 |
Mifflin, Steven W |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Hybrid Atomic Force-Optical Imaging System to Investigate Prenatal Nicotine @ University of North Texas Hlth Sci Ctr
DESCRIPTION (provided by applicant): Neuronal nicotinic acetylcholine receptors (nAchR) are targets for the neurotransmitter acetylcholine and exogenous cholinergic ligands such as nicotine from cigarette smoke. Nicotinic receptors are expressed on peripheral (carotid body) and central (brainstem neurons) structures that are involved in mediating the respiratory responses to hypoxia. Prenatal nicotine destabilizes breathing, diminishes the compensatory respiratory response to hypoxic stress and contributes to sudden infant death syndrome (SIDS). One aspect of the maladaptive respiratory response to nicotine exposure appears to be mediated by a reduction in central GABAergic regulation of respiratory rhythm formation. This results, in part, from the "loss-of-function" of nAchR subunits. The overall goal of this proposal is to develop a novel imaging system which combines atomic force microscopy (AFM) and high-speed optical imaging to investigate the effect of nicotine on the development and stability of breathing rhythms in response to hypoxia. We propose to use this hybrid imaging system to determine whether prenatal nicotine alters synaptic transmission in central respiratory circuits responsible for generating breathing rhythms. The specific aims are: 1. Identify nicotine-induced changes the spatiotemporal patterns of central respiratory network activity using optical imaging. Based on Preliminary studies, we hypothesize that prenatal exposure to nicotine will alter the spatial and temporal patterns of central respiratory activity during hypoxic stimulation and will reduce the ability to autoresuscitate. 2. Evaluate the effect of nicotine on the binding properties of 17 and 14 nAchRs using atomic force microscopy. Based on Preliminary studies, we hypothesize that prenatal nicotine will reduce the binding probability of 17 and 14 subunit containing nAchR expressed on central respiratory neurons. Results obtained from this proposal are significant because they will be the first to directly visualize nicotine-induced changes in the spatiotemporal patterns of neuronal activity in key populations of central respiratory neurons using a preparation that preserves pontomedullary respiratory circuitry. Experiments outlined in this proposal will also provide new insight to the deleterious affects of prenatal nicotine on the functional binding properties of nAchRs. These new findings may aid in developing clinical recommendations to alleviate hypoxic-induced respiratory depression associated with the incidence of SIDS and other prenatal respiratory disorders. PUBLIC HEALTH RELEVANCE: Prenatal exposure to nicotine from cigarette smoke predisposes infants to sudden infant death syndrome (SIDS). Recent scientific evidence strongly suggests that nicotine may predispose infants to SIDS by causing excessive activation of nicotinic receptors on brain cells that control breathing. The goal of this proposal is to determine the effect of prenatal nicotine exposure on the control of breathing by the brain. Knowledge of the effects of nicotine on respiratory neurons is important since the pathogenesis of SIDS remains incompletely understood, and thus, severely limits potential pharmacological targets and treatment strategies. It is also of clinical significance since nicotine replacement therapy for pregnant women is often regarded as a safe alternative in smoking cessation programs.
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0.926 |
2008 — 2012 |
Mifflin, Steven W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neurohumoral Adaptations to Chronic Intermittent Hypoxia @ University of North Texas Hlth Sci Ctr
DESCRIPTION (provided by applicant): Sleep apnea poses a significant health risk and has rapidly gained recognition as a common co-morbid factor in patients diagnosed with metabolic syndrome. Epidemiological studies have revealed a strong association between sleep apnea and increased blood pressure and exaggerated sympathetic nerve discharge, even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive bouts of arterial hypoxemia that occur during sleep apnea. Rats exposed to CIH develop a persistently increased blood pressure as observed in humans with sleep apnea. There is a surprising paucity of information concerning how sleep apnea and CIH alter synaptic processing among sympathetic regulatory neurons and how these alterations lead to a persistent rise in sympathetic nerve discharge and a sustained increase in blood pressure. The Program objectives are to address mechanisms within the central nervous system that mediate CIH-induced hypertension and elevated sympathetic nervous system activity and to provide insights into potential therapeutic targets and strategies. Our work has demonstrated that the persistent increase in blood pressure during the first 7 days of exposure to CIH is dependent upon arterial chemoreceptors and angiotensin (ANG II) acting within the forebrain. Three projects are proposed which will utilize state-of-the-art neuroanatomical, in vivo and in vitro electrophysiological and molecular approaches to provide a comprehensive analysis of the central circuitry mediating the persistent increase in blood pressure induced by CIH. Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CIH induces activity-dependent changes in neurons in the nucleus of the solitary tract (NTS) that regulate sympathetic and HPA axis function. Project 2, led by T. Cunningham, will test the hypothesis that increased activity of the renin-angiotensin system during CIH induces activity-dependent changes in neurons in the lamina terminalis that project to the PVN and increase sympathetic outflow. Project 3, led by G. Toney, will test the hypothesis that chemoreceptor- and ANG ll-sensitive inputs induce activity-dependent changes in sympatho-excitatory PVN neurons that increase their discharge and excitability. Achieving the goals of these projects will be facilitated by 4 Core facilities (Administrative, Animal, Neuroanatomy, Biochemical/Molecular). The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. The proposed studies will identify sites and mechanisms that could be beneficial therapeutic targets in sleep apnea patients. The results will also have relevance to our understanding of other conditions associated with central nervous system hypoxia (heart failure, stroke) and other sodium-dependent and ANG ll-dependent models of hypertension (obesity).
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0.926 |
2015 — 2019 |
Mifflin, Steven W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Administrative Core A @ University of North Texas Hlth Sci Ctr
Core A Abstract The Administrative Core will provide administrative and scientific oversight to all members of the Program Project Grant (PPG). The primary objective of the Administrative Core is to provide overall administrative support to the program, including efficient use of resources, providing feedback and oversight of cores to ensure quality and prioritize access, facilitating communication among projects and cores, and coordinating the meetings of the advisory committees. These activities will be under the direction of Dr. Steve Mifflin and he will be assisted by an administrative secretary (Ms. Marquez) and business administrator (Ms. Henson) with extensive experience in coordinating and managing the activities of multidisciplinary groups.
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0.926 |
2015 — 2019 |
Mifflin, Steven W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neurohumoral Adaptations Induced by Intermittent Hypoxia Lead to Enhanced Chemoreflex Drive and Persistent Sympatho-Excitation @ University of North Texas Hlth Sci Ctr
Project 1 Abstract According to a National Sleep Foundation study, 31% of men and 21% of women in the US are at high risk of suffering from sleep apnea (SA). There is a cause-and-effect relationship between SA and increased mean arterial pressure (MAP) and increased sympathetic nerve discharge (SND) which persist even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during SA. CIH in animals results in an increased MAP and SND as seen in human SA patients. CIH also enhances the hypothalamic-pituitary-adrenal axis response to stress. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors during CIH increases the discharge of and the responsiveness of catecholaminergic and glutamatergic neurons in the nucleus of the solitary tract (NTS) and this provides a sympatho-excitatory drive that underlies the CIH-induced persistent increase in MAP and SND. Three specific aims are proposed to further test this hypothesis. Specific Aim 1 will test the hypothesis that during 7 and 28 days exposure to CIH and CIHHC, arterial chemoreceptor afferents stimulate NTS A2 neurons which activate the HPA axis and induce release of CORT. CORT then enhances glutamatergic transmission to NTS which contributes to the CIH-induced sustained increase in MAP and SND. Specific Aim 2 will test the hypothesis that following 7 & 28 days CIH and CIHHC, descending CRF inputs from PVN provide an excitatory drive to catecholaminergic and glutamatergic NTS neurons that contributes to the sustained increase in MAP and SND. Specific Aim 3 will test the hypothesis that the resistance of NTS neurons to ischemic injury is reduced following 7 & 28 days CIH and CIHHC due to changes in KATP currents. The results of these studies will provide a comprehensive analysis from the system to the cellular level of neuronal and humoral adaptations to CIH will provide new insights into the mechanisms whereby CIH leads to elevated MAP and SND.
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0.926 |
2015 — 2019 |
Mifflin, Steven W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neurohumoral Adaptations to Chronic Intermittent Hypoxia: Insights Into the Pathophysiology of Sleep Apnea @ University of North Texas Hlth Sci Ctr
? DESCRIPTION (provided by applicant): Sleep apnea poses a significant health risk and is associated with increased blood pressure and exaggerated sympathetic nerve discharged. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive bouts of arterial hypoxemia that occur during sleep apnea. Rats exposed to CIH develop a persistently elevated blood pressure and sympathetic outflow as observed in humans with sleep apnea. During the past funding period our program provided novel insights into how CIH alters synaptic processing among sympathetic regulatory neurons in the central nervous system and how these alterations lead to a persistent rise in sympathetic nerve discharge and a sustained increase in blood pressure. The Program objectives are to address mechanisms within the central nervous system that mediate CIH-induced hypertension and elevated sympathetic nervous system activity and to provide insights into potential therapeutic targets and strategies. Our work has demonstrated that the persistent increase in blood pressure during the first 7 days of exposure to CIH is dependent upon arterial chemoreceptor, the HPA axis and angiotensin (ANG II) acting within the forebrain. Three projects are proposed: Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CH induces activity-dependent changes in neurons in the nucleus of the solitary tract (NTS) that regulate sympathetic and HPA axis function. Project 2, led by T. Cunningham, will test the hypothesis that increased activity of the renin-angiotensin system during CIH induces activity-dependent changes in neurons in the lamina terminalis that project to the PVN and increase sympathetic outflow. Project 3, led by G. Toney, will test the hypothesis that chemoreceptor- and ANG ll-sensitive inputs induce activity dependent changes in sympatho-excitatory PVN neurons that increase their discharge and excitability and that these adaptations may actually be protective when faced with ischemia. Achieving the goals of these projects will be facilitated by 2 Core facilities (Administrative, Analytical). The Analytical Core will provide genomic and proteomic analysis of gene expression and protein levels as well as post-translational modifications of proteins. The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. The results will also have relevance to our understanding of other conditions associated with central nervous system hypoxia (heart failure, stroke) and other sodium dependent and ANG ll-dependent models of hypertension (obesity).
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0.926 |