1985 — 1986 |
Felder, Robert B |
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 Studies of Cardiac Vagal Reflexes
This investigator is engaged in a long term effort to define the neurophysiological mechanisms and anatomical interconnections of central neurons subserving cardiovascular reflex control. The present studies will focus on both afferent and efferent limbs of the vagal innervation of the heart. Initial studies of afferent projections will use horseradish peroxidase (HRP) techniques to determine the general locations of cardiac vagal afferent cell bodies in the nodose gnaglion and to define the regions of the nucleus tractus solitarius (NTS) in which their central projections terminate. In subsequent electrophysiological studies, single unit recordings from the cell bodies of cardiac vagal afferents will be obtained, and antidromic central stimulation will be used to determine whether specific fiber types terminate on different cell populations in NTS. In addition, the hypothesis of a presynaptic interaction between afferent inputs to NTS neurons will be tested by observing the effect of electrically stimulating other peripheral cardiovascular afferent nerves (e.g., aortic or carotid sinus) on the threshold for antidromic activation of the central endings of single vagal afferent neurons. Studies of efferent vagal mechanisms will evaluate the significance of the recent observation that vagal neurons controlling heart rate reside in two specific brain stem areas--the nucleus ambiguus (NA) and the dorsal motor nucleus (DMN). The hypothesis that these neurons selectively process afferent input from different receptor groups will be tested by recording from units in each area during manipulation of afferent input from selected cardiovascular receptors. Emphasis in these studies will be on the manner in which neurons in both nuclei process physiologic input from carotid sinus and left ventricular baroreceptors alone and in combination. Intracellular iontophoresis of HRP will be used to fill the dendritic trees of some of these cells to determine the extent of their anatomical connections with other brain stem regions involved in cardiovascular reflexes. These studies will provide new insight into central mechanisms influencing vagal control of heart rate in normal animals.
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1988 — 1996 |
Felder, Robert B |
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 Integrative Mechanisms in Nts |
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1998 — 2002 |
Felder, Robert B |
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. |
Brain Stem Mechanisms Mediating the Nociceptive Pressor Response
The goal of this proposal is to determine the role of the lateral parabrachial nucleus (LPBN) in mediating the cardiovascular responses to pain. Noxious stimulation typically elicits increases in arterial blood pressure and heart rate. These responses are mediated by nociceptive and cardiovascular centers in the brain stem. Recent anatomical and electrophysiological studies point to the LPBN as the major projection site for nociceptive inputs from lamina I and lamina II neurons in the spinal cord and the spinal trigeminal sensory nucleus in medulla. Moreover calcitonin gene-related peptide (CGRP) and substance P (SP), neuropeptides prominently involved in sensory afferent and nociceptive pathways, are present in LPBN and have been implicated in ascending pain pathways. These studies will use single cell electrophysiological recording techniques, recordings of arterial pressure, heart rate and sympathetic nerve activity, and functional neuroanatomy (c-fos) to determine the role of the LPBN in mediating the nociceptive pressor response by stimulating the trigeminal afferent system which has a discrete termination site in caudal medulla and well defined projection pathways to LPBN. The influence of the solitary tract nucleus (NTS) will also be examined, though existing data suggest a secondary role for NTS in this process. Finally, the interactions of baroreceptor afferent signals with noxious inputs will be determined at LPBN and at the rostral ventrolateral medulla (RVLM), the medullary sympathetic outflow site for the pressor response. The trigeminal afferent system mediates a number of important clinical pain syndromes, including migraine headache, the headache of arachnoid hemorrhage, trigeminal neuralgia, temporal mandibular joint pain and corneal and oral cavity pain. Thus, a better understanding of the central neural mechanisms mediating cardiovascular responses to noxious trigeminal stimulation may ultimately lead to new management strategies for patients with these clinical syndromes. In addition, these findings will contribute to the basic understanding of the central link between nociceptive afferent signals and cardiovascular regulation.
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1998 — 2002 |
Felder, Robert B |
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. |
Hypothalamic Neuropeptide Pathways Mediating Sympathetic Responses to Leptin
Circulating leptin produced by adipocytes influences feeding behavior and metabolic processes through its effects on the central nervous system. Recent studies have implicated hypothalamic neuropeptide Y (NPY), corticotrophin releasing factor (CRF) and the melanocortins in these processes. Our preliminary data indicate that leptin increases sympathetic nerve activity (SNA) to intrascapular brown adipose tissue (IBAT), adrenal gland (Adr), kidney, and skeletal muscle. Leptin affects feeding behavior via its receptors (OB-Rb) in the hypothalamus, which is also an important site driving the sympathetic nervous system. However, the mechanisms by which leptin initiates sympathetic excitation have not been determined. The Orexigenic peptide NPY inhibits IBAT SNA when microinjected into the paraventricular nucleus (PVN) of hypothalamus and thus may modulate the activity of sympathoexcitatory PVN neurons. We hypothesize that the excitation of these neurons is mediated by alpha melanocyte stimulating hormone (alpha-MSH), acting on the MC4-R receptors have recently been found to suppress feeding behavior, and that leptin permits this excitation by its known effect of reducing hypothalamic NPY and NPY release in PVN. We also hypothesize that leptin induced sympathoexcitation is mediated, at least in part, by CRF-containing PVN neurons projecting to brain stem and spinal cord. Three neural control laboratories will collaborate in testing these hypotheses. Dr. Mark's lab will test the effect of circulating leptin on IBAT, Adr and renal SNA after discrete hypothalamic lesions and regional microinjections of peptides (alpha-MSH and NPY) and peptide antagonists into critical hypothalamic subnuclei. Dr. Felder's lab will test the effects of NPY and alpha-MSH on single PVN neurons, and their role in mediating PVN neuronal responses to leptin infusion. Dr. Johnson's lab will use immunohistochemical and microinjection techniques to determine the role of descending CRF- containing PVN neurons in mediating the responses to intravenous leptin. These studies will provide important new insights into the link between leptin, a humoral signal generated in adipose tissue, and activation of autonomic mechanisms regulating peripheral metabolic function.
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2001 — 2005 |
Felder, Robert B |
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. |
Angiotensin and Central Neurohumoral Activation in Chf
In congestive heart failure (CHF), increased sympathetic drive and reduced renal perfusion activate the peripheral renin-angiotensin-aldosterone-system (RAAS). The resulting peripheral vasoconstriction and sodium and water retention by the kidneys precipitate further clinical deterioration by increasing the stress on the already failing ventricle. These peripheral effects of RAAS activation have been the targets of successful therapeutic interventions (afterload reduction and volume control) in heart failure. Nevertheless, the clinical course of heart failure is progressive, the long-term prognosis remains dismal, and the search for innovative approaches to therapy continues. Angiotensin II (ANGII) has prominent central nervous system (CNS) effects on fluid balance and sympathetic drive that have been well studied in the context of hypertension, but have been largely overlooked in heart failure. The hypothesis of the proposed studies is that the CNS effects of high circulating ANGII contribute substantially to the augmented sympathetic drive and fluid accumulation that characterize the late stage of established heart failure. Secondary hypotheses are that these CNS effects of ANGII are exacerbated by high aldosterone levels, and opposed by high levels of atrial natriuretic peptide (ANP), secreted by the failing heart. The model to be studied is left ventricular dysfunction caused by proximal occlusion of a coronary artery in the rat, simulating the most common cause of heart failure in humans. Extent of left ventricular dysfunction will be determined by echocardiography and confirmed anatomically. The specific aims are to determine whether, in rats with CHF: 1) forebrain mechanisms activated by high levels of circulating neuropeptides contribute to augmented neurohumoral drive, 2) blood-borne neuropeptides acting on forebrain circumventricular organs alter the balance of excitatory and inhibitory neurotransmitter systems in the paraventricular nucleus of the hypothalamus to favor neurohumoral excitation. This work will provide new information concerning the role of the central nervous system in the pathophysiology of CHF and will draw attention to the possibility of CNS directed drug therapy for heart failure.
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2003 — 2006 |
Felder, Robert B |
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. |
Cytokine and Sympathetic Drive in Heart Failure
Immune system activation (ISA) is a commonly recognized component of the heart failure syndrome. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-lbeta)- the blood borne products of ISA- activate the sympathetic nervous system. The overall hypothesis of this project is that these pro-inflammatory cytokines contribute to the augmented sympathetic drive in heart failure by their actions upon neurons in the paraventricular nucleus (PVN) of the hypothalamus. Two principal mechanisms for this proposed effect will be investigated. 1) Circulating cytokines induce catecholamine release in PVN. Increased catecholamine content in PVN has been associated with heightened sympathetic drive in other pathophysiologicalconditions, such as neurogenic hypertension, that are also characterized by increased activity of the renin-angiotensinsystem (RAS). The present studies will examine the hypothesis that catecholamine release in PVN, induced by circulating cytokines, activates sympatho-excitatory PVN neurons, and that this effect is facilitated by interactions in PVN between catecholamines and the RAS. 2) Cytokines induce the production of reactive oxygen species (ROS). Cytokines may be produced in the brain, and may enter the brain via a saturable membrane transport system. The present studies will examine the hypothesisthat in heart failure the presence of cytokines in the PVN induces ROS, which activates sympatho-excitatory PVN neurons. Finally, these studies will examine the mechanisms by which activation of PVN neurons by circulating or intrinsic cytokines might elicit an increase in sympathetic drive. Recent evidence suggests that signals descending from PVN require activation of an angiotensin type 1 receptor in rostral ventrolateral medulla (RVLM) to effect an increase in sympathetic drive. The present studies will determine whether sympatho-excitatoryPVN neurons activated by pro-inflammatory cytokines utilize this pathway. Electrophysiologicalrecordingtechniques will be used in conjunction with push-pull analysis of peptide/transmitter release and immunohistochemistry to test these hypotheses in rats with ischemia-induced heart failure and in sham-operated controls. These studies will provide important new insightsinto the role of the pro-inflammatorycytokines in heart failure.
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2003 — 2017 |
Felder, Robert B |
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. |
Cytokines and Sympathetic Activation in Heart Failure
DESCRIPTION (provided by applicant): Systolic heart failure (HF) is a devastating condition with high socioeconomic impact. Progress in the development of new pharmacological agents to treat HF is stagnant. Standard therapy targets the untoward peripheral effects of the heightened activity of the renin-angiotensin- system (RAS) and sympathetic nervous system (SNS), compensatory mechanisms that seek to maintain pressure in the face of a low cardiac output. As yet, there is no specific therapy for the inflammatory state that accompanies HF and contributes to adverse outcomes. Large clinical trials demonstrated no benefit of anti-cytokine agents, which can have serious side effects. Recent studies have revealed that the central nervous system actions of pro-inflammatory cytokines (PICs) contribute to the pathogenesis of HF - in particular, to the detrimental increase in sympathetic nerve activity. That work has focused almost exclusively on the effects of PICs inside the blood-brain barrier (BBB), with little attention to the effects of circulating PICs that reflect the peripheral inflammatory state but are too large to cross the BBB. Our preliminary studies demonstrate that blood-borne PICs act upon the subfornical organ (SFO), a forebrain circumventricular organ that lacks a BBB, to increase sympathetic activity in normal rats. We hypothesize that the high circulating levels of PICs in HF induce an inflammatory/excitatory state in the SFO that drives inflammatory/excitatory mechanisms downstream in the hypothalamic paraventricular nucleus (PVN) to increase peripheral sympathetic nerve activity. Since PIC receptors mediate molecular rather than synaptic events, their effects on the SFO are likely mediated by upregulation of intracellular signaling mechanisms related to RAS, reactive oxygen species, and endoplasmic reticulum stress. The proposed studies will: 1) determine the contribution of tumor necrosis factor (TNF)-a and interleukin (IL)-1b, acting upon their receptors in SFO, to sympathetic excitation in normal rat and rats with HF; 2) identify the cellular and molecular mechanisms activated in the SFO by TNF-a and IL-1b, and their impact on cellular and molecular mechanisms downstream in PVN; 3) determine whether counteracting the effects of PICs at the SFO level is a viable potential therapeutic strategy to reduce sympathetic excitation and its consequences in HF. A combination of molecular, immunohistochemical, and in vivo electrophysiological and hemodynamic recording techniques will be used to elucidate the mechanisms by which blood-borne PICs, acting on the SFO, influence neurohumoral excitation. Since the SFO lacks a BBB, these studies may identify targets for therapeutic intervention in the inflammatory process in HF that are accessible to systemic drug administration.
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2011 — 2014 |
Felder, Robert B |
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 Map Kinases - Substrate For Sympathetic Excitation in Heart Failure
DESCRIPTION (provided by applicant): Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Over activity of the sympathetic nervous system (SNS) is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. Recent studies suggest that altered neurochemical mechanisms in the brain contribute to the augmented SNS activity in heart failure. Several excitatory substances appear in the brain in excess quantities in heart failure. These include angiotensin II (ANG II), aldosterone (ALDO) and the pro-inflammatory cytokines (PIC). All three act to increase the production of reactive oxygen species in the brain, but beyond that it is not at all clear how they activate the SNS. We recently found that blocking one of the three major components of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade in the brain substantially reduced SNS activity in rats with heart failure. These MAPKs are sensitive to the presence of reactive oxygen species, respond to ANG II, ALDO and PIC, and, when activated, lead to the production of more excitatory neurochemical substances that may contribute to persistent activation of the SNS, which is typical of heart failure. The overall goal of this project is to determine to what extent the three major MAPK signaling pathways contribute to the excitatory neurochemical milieu in a key cardiovascular regulatory center of the brain, the paraventricular nucleus of hypothalamus (PVN) that drives SNS activity in heart failure. In rats with systolic heart failure and in normal rats treated with ANG II, ALDO and PIC to induce MAPK activity, we will determine: 1) the effects of the three major MAPK signaling pathways on the expression of excitatory mediators in the PVN;2) the effects of MAPK signaling in the PVN on SNS activity;3) the phenotypes of the cells in PVN - neurons, microglia, astrocytes, and perivascular macrophages - that express MAPK signaling, and their influences on the production of excitatory mediators and sympathetic excitation. A combination of molecular, immunohistochemical, and electrophysiological techniques will be used to elucidate the mechanisms by which brain MAPK signaling influences SNS activity. We hope these studies will identify novel targets for therapeutic intervention in systolic heart failure. PUBLIC HEALTH RELEVANCE: This project examines the role of a critical intracellular signaling mechanism, the mitogen-activated protein kinases, in the upregulation of excitatory mediators (angiotensin II, aldosterone, and pro-inflammatory cytokines) in the brain, and the subsequent activation of the sympathetic nervous system, in a rat model of systolic heart failure. Learning more about the central nervous system mechanisms regulating sympathetic drive in heart failure may help identify novel approaches to the treatment of this devastating disorder.
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2017 — 2020 |
Felder, Robert B |
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 Erk1/2 Signaling and Sympathetic Excitation in Heart Failure
Heart failure with impaired systolic function (HF) is a common malady of the aging population, with dire personal and socioeconomic consequences. The past 2 decades have seen little progress in the development of new pharmaceutical agents to treat HF. A major factor contributing to the progression of HF and adverse outcomes is exaggerated sympathetic nervous system activity. Current pharmacological treatments for HF target the peripheral effects of this augmented sympathetic nerve activity, but not the central nervous system source. Recent studies in my laboratory have implicated the extracellular signal- regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway as an obligatory step leading to sympathetic excitation by many of the neurochemicals (i.e., angiotensin II, aldosterone, pro-inflammatory cytokines) that are known to be upregulated in key cardiovascular regulatory regions of the HF brain ? effectively acting as a final common pathway for these excitatory agonists. Working with a rat model of ischemia-induced HF that closely mimics systolic HF in humans, we found that reducing brain ERK1/2 activity in these regions ? and in particular in the hypothalamic paraventricular nucleus which is a source of presympathetic neurons ? reduces sympathetic nerve activity and ameliorates the peripheral manifestations of HF. In addition, our preliminary studies suggest that this molecular pathway is amenable to treatment with peripherally administered drug-loaded microparticle preparations. The present proposal will address both basic mechanistic and potential therapeutic aspects of this molecular pathway. The mechanistic studies will focus specifically on the role of ERK1/2 signaling in the hypothalamic paraventricular nucleus, a locus of presympathetic neurons known to contribute to augmented sympathetic nerve activity in HF. We will examine the role of the epidermal growth factor receptor as a putative ?gateway? to the ERK1/2 signaling pathway by multiple excitatory agonists, the effect of ERK1/2 signaling on transcription factors that upregulate the expression of excitatory agonists, the effect of ERK1/2 signaling on a potassium channel mechanisms that may increase the excitability of presympathetic neurons. The therapeutic studies will explore the possibility that an advanced drug delivery system that facilitates passage of drug across the blood brain barrier can reduce brain ERK1/2 signaling and thereby reduce sympathetic nerve activity to improve peripheral manifestations of HF and survival in HF - a critical translational issue. We anticipate that these studies will lead to better understanding of the role of brain ERK1/2 signaling in sympathetic excitation and will lay the groundwork for the development of novel pharmacological approaches to the treatment of HF.
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