2003 — 2005 |
Stocker, Sean D |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Forebrain Neurohumoral Integration in Heart Failure @ University of Texas Hlth Sci Ctr San Ant
[unreadable] DESCRIPTION (provided by applicant): Elevated circulating angiotensin II (ANG II) and plasma osmolality excite neurons in the forebrain lamina terminalis including the nucleus medianus (NM or median preoptic nucleus) and increase sympathetic nerve activity (SNA). Additionally, NM neurons receive direct projections from catecholaminergic cell populations in the hindbrain and plays an important role in the regulation of intravascular volume. Clinical features of low cardiac output congestive heart failure (CHF) are a chronic accumulation of water and sodium, significant increases in plasma ANG II and aldosterone levels, and elevated SNA. Several studies demonstrate that central or peripheral blockade of ANG II or mineralocorticoid receptors and peripheral blockade of ANG II production leads to profound reductions in SNA. Thus, increases in circulating ANG II and/or plasma sodium appear to act at forebrain lamina terminalis neurons to increase SNA during CHF. The overall concept of the present proposal is that NM neurons projecting to the paraventricular nucleus of the hypothalamus integrate information regarding plasma ANG II levels, osmolality, and intravascular volume, and this integration is altered in rats with CHF. It is noteworthy that the cardiopulmonary reflex is attenuated in rats with CHF, and lesions of the NM attenuate several responses to changes in intravascular volume. Thus, CHF may be associated with reduced responsiveness of NM neurons to cardiopulmonary inputs thereby contributing to the increase in SNA observed in the presence of increased circulating ANG II. The proposed experiments will be performed in vivo using extracellular recordings to determine the integrated response of individual NM neurons to peripheral ANG II, osmotic, and cardiopulmonary receptor afferent input. The specific aims are: (1) determine whether individual NM neurons receive both peripheral ANG II and osmotic input and identify the receptors that mediate these responses, (2) determine whether osmo- or peripheral ANG II-sensitive NM neurons also receive cardiopulmonary input and whether these ascending inputs are mediated by noradrenergic receptor activation, (3) determine whether the basal activity and/or responses of NM neurons to these inputs are altered in rats with established CHF. [unreadable] [unreadable]
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0.955 |
2008 — 2012 |
Stocker, Sean D |
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. |
Central Nervous System Mechanisms of Obesity Hypertension
[unreadable] DESCRIPTION (provided by applicant): Risk estimates from the Framingham Heart Study indicate that ~75% of essential hypertension in men and 65% of essential hypertension in women is largely attributed to excess body weight and obesity. Convincing evidence from both clinical studies and animal models demonstrates that elevated sympathetic outflow to the kidney and hindlimb vasculature plays a pivotal role in the pathogenesis of obesity-induced hypertension. Despite the important relationship between body weight or adiposity and activation of the sympathetic nervous system, little is known regarding the neural pathways and cellular mechanisms that underlie the sustained increase in sympathetic outflow and arterial blood pressure during obesity. The long term goal of our laboratory is to identify the neural pathways and cellular mechanisms that increase sympathetic outflow and blood pressure in obesity. Two afferent signals to the brain postulated to mediate the elevated sympathetic outflow and blood pressure in obesity are hyperinsulinemia and hyperleptinemia. Our working hypothesis is that diet-induced obesity increases circulating insulin and leptin to activate a descending circuit from the arcuate nucleus to the hypothalamic paraventricular nucleus. Subsequent receptor activation in the hypothalamus increases the discharge of sympathetic neurons in the hypothalamic paraventricular nucleus to enhance excitatory drive to the brainstem and spinal cord. This enhanced excitatory drive increases sympathetic outflow and arterial blood pressure. In this application, we will use state-or-the-art electrophysiological approaches to identify the central mechanisms that support obesity-induced hypertension. Specific aim 1 will identify the cellular mechanisms within the hypothalamic paraventricular nucleus by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 2 will identify the cellular mechanisms within the rostral ventrolateral medulla by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 3 will identify the mechanisms within the hypothalamic paraventricular nucleus and rostral ventrolateral medulla that support the elevated sympathetic outflow and blood pressure in a rodent model of diet-induced obesity. Our rationale for this project is that identification of the neural pathways and mechanisms that mediate the sympathoexcitatory actions of insulin and leptin, and how these pathways ultimately contribute to obesity-induced hypertension will provide a framework for the development of novel therapeutic treatments. [unreadable] [unreadable] [unreadable]
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0.961 |
2016 — 2019 |
Farquhar, William B [⬀] Stocker, Sean D |
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. |
Adverse Neurogenic Actions of Dietary Salt
? DESCRIPTION (provided by applicant): Excess dietary salt causes target organ damage and increases the risk for adverse cardiovascular (CV) events independent of blood pressure (BP). Recent data in salt-resistant, normotensive rodents suggest that high dietary salt enhances the excitability or gain of sympathetic circuits, exaggerates sympathetic and CV responses to various stimuli, and increases BP variability (BPV). There are limited data regarding the impact of dietary salt intake on sympathetic nerve activity (SNA) and CV function in salt-resistant humans as well as the underlying mechanisms contributing to these adverse effects. Our long-term goal is to determine how dietary salt adversely affects BP regulation and CV health. The objective of this proposal is 2-fold: (1) to comprehensively evaluate the impact of dietary salt intake on SNA and CV reactivity and BPV in normotensive humans, and (2) to identify novel mechanisms underlying these adverse neurogenic effects of dietary salt using salt-resistant rodents. Our working hypothesis is that high dietary salt elevates plasma [Na+] to activate forebrain osmoreceptors via the epithelial sodium channel (ENaC). This subsequently sensitizes neurons of the rostral ventrolateral medulla (RVLM) through a local activation of angiotensin II type 1 receptor (AT1R) and decrease in resting K+ conductance. In turn, both human subjects and animals have exaggerated SNA and BP responses to a variety of stimuli thereby leading to increased BPV and greater risk for adverse CV events. We will test this hypothesis through 4 specific aims: 1) Aim 1 will test the hypothesis that high dietary salt increases SNA and CV reactivity in normotensive adults, 2) Aim 2 will test the hypothesis that high dietary salt increases BPV in normotensive adults, 3) Aim 3 will determine the extent by which a high salt diet induces neuroplasticity and alterations in membrane properties of RVLM neurons via local activation of AT1R to exaggerate SNA reflexes and increase BPV, and 4) Aim 4 will determine the extent by which changes in plasma sodium concentration and ENaC alter RVLM neurons and exaggerate SNA reflexes and increase BPV. To address both objectives through these aims, we have established a unique multi-institutional, multi-PI collaboration that includes a human CV physiologist and an animal neurophysiologist. This combination uniquely positions the research team to readily translate findings in animal models to humans and impact CV health. The expected outcome is to definitively demonstrate that dietary salt loading increases CV reactivity and BPV through a sympathetic nervous system mechanism that originates in the brain. The proposed research is significant, as these studies will provide empirical evidence that dietary salt intake impacts neurohumoral control of the circulation in salt-resistant humans. In addition, the proposed studies in rodents will identify novel mechanisms underlying these adverse effects and thereby create a platform for new therapeutic targets. The proposed research is innovative because it will identify a novel neurogenic action of dietary salt in human CV regulation.
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0.961 |
2019 — 2021 |
Stocker, Sean D |
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. |
Brain Nacl-Sensing in Salt-Sensitive Hypertension. @ University of Pittsburgh At Pittsburgh
PROJECT SUMMARY Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Time-controlled studies in both humans and rodents suggest a high salt diet elevates plasma or cerebrospinal fluid (CSF) [NaCl] by 2-5mM to activate specialized NaCl-sensing neurons located in hypothalamic circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Interestingly, central infusion of non-voltage gated sodium channel antagonists attenuates every experimental model of salt-sensitive hypertension tested to date. These antagonists target acid sensing ion channel, sodium hydrogen exchanger, sodium calcium pump, and the epithelial sodium channel. In light of preliminary findings, our working hypothesis is that a high salt diet elevates extracellular [NaCl] to activate NaCl-sensitive neurons of the OVLT through a unique epithelial sodium channel (ENaC) expressing ?? subunits. The NaCl-sensitivity of these ENaC neurons and sympathoexcitatory responses are enhanced by circulating factors such as angiotensin II and aldosterone. Subsequent activation of descending pathways increases SNA and ABP. This hypothesis will be tested through 3 specific aims: 1) determine the extent by which ENaC subunits mediate the intrinsic NaCl-sensitivity of OVLT neurons and sympathoexcitatory responses to an acute NaCl load, 2) determine whether angiotensin II enhances the NaCl-sensitivity of ENaC-positive neurons in the OVLT and the extent by which these neurons contribute to angiotensin II-salt hypertension, and 3) determine the extent by which aldosterone and deoxycorticosterone-salt hypertension alter ENaC expression, enhance NaCl-sensitivity and depend on ENaC subunits of the OVLT. Our rationale for this project is that identification of the cellular elements that underlie NaCl- sensing in the brain will provide a framework for the development of novel therapeutic treatments of salt-sensitive hypertension.
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1 |
2020 — 2021 |
Stocker, Sean D |
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. |
Identification of Mechano Versus Chemo-Sensitive Renal Sensory Neurons in Hypertension @ University of Pittsburgh At Pittsburgh
ABSTRACT Renal denervation lowers arterial blood pressure in multiple clinical trials and experimental animal models of hypertension. These anti-hypertensive effects have been partly attributed to the removal of renal sensory nerves as selective denervation of renal sensory nerves lowers arterial blood pressure to the same extent as total renal denervation. Despite our current knowledge of renal nerves, there is a severe lack of anatomical, functional, and mechanistic knowledge about the specific sensory fiber-types responsible for cardiovascular control. Renal sensory nerves detect mechanical and chemical stimuli within the kidneys and consequently alter sodium reabsorption, renin secretion, and sympathetic outflow. These responses are dependent on mechano- and chemo- sensitive nerve fibers which have not been clearly defined. Our preliminary data using single-cell transcriptomics on renal sensory neurons demonstrates the existence of two distinct populations: the mechanosensitive channel Piezo2 and chemosensitive channel TRPV1. The overall hypothesis of this proposal is that neurochemically distinct populations of renal sensory neurons expressing Piezo2 and TRPV1 mediate mechano- and chemo-sensitive responses in the kidney. The neurochemical profile of these neurons switches in renal stenosis from a loss of Piezo2-mechanosensitive fibers to robust expression and increased sensitivity of TRPV1-chemosensitive fibers to elevated sympathetic outflow and arterial blood pressure. Aim 1 will employ in vivo single-unit recordings, single-cell transcriptomics (>40 sensory genes), and optogenetics to determine the extent by which Piezo2 and TRPV1-expressing neurons represent mechano- and chemo- sensitive renal sensory nerve populations. Aim 2 will determine how hypertension produced by renal stenosis alters the mechano- versus chemosensitivity of renal afferents, the neurochemical profile of sensory neurons, and the sensory innervation of the kidney. Aim 3 will directly assess the contribution of Piezo2 versus TRPV1 renal sensory fibers and channels to renal sensory function and renovascular hypertension. This proposal will define, for the first time, the neurochemical and functional phenotype of renal sensory nerve populations involved in the control of arterial blood pressure, anatomically map innervation sites in the kidney, and functionally test distinct renal afferent fibers populations and channels in vivo that have a pathological role of hypertension.
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1 |