Paul E. Sawchenko - US grants
Affiliations: | Laboratory of Neuronal Structure and Function | Salk Institute for Biological Studies, La Jolla, CA, United States | |
Neurosciences | University of California, San Diego, La Jolla, CA |
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High-probability grants
According to our matching algorithm, Paul E. Sawchenko is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1985 — 1996 | Sawchenko, Paul E. | 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. |
Neuropeptide Co-Expression in the Hypothalamus @ Salk Institute For Biological Studies The proposed neuroanatomical studies employ immunohistochemical and hybridization histochemical methods to clarify the roles of particular hormonal and neural influences in regulating the expression of multiple neuroactive peptides that cohabit neurosecretory neuron populations in the rat hypothalamus. Parvocellular neurons that produce corticotropin-releasing factor for the initiation of pituitary-adrenal responses to stress, and magnocellular neurosecretory neurons that synthesize the peptide hormones oxytocin or vasopressin (which play roles reproduction and body water balance, respectively), are both known to express a number of additional neuropeptides. Differential effects of alterations in steroid hormones status have been described for both class of neurons. The proposed studies will address the following issues: 1. Non-steroidal influences on the CRF neuron. Evidence for roles of circulating corticotropin, thyroid hormones, and as yet unspecified stimuli associated with lactation will be characterized as to their effects on levels of co-existing peptides, their sites of action and/or whether effects on gene expression are involved. 2. Role of neural inputs in influencing peptide expression in the CRF neuron. The roles of projections arising from brainstem catecholamine neurons, the hippocampal formation, and the basal forebrain in mediating peptide dynamics in the CRF neuron, and\or in mediating the feedback effects of steroids will be assessed. The role of aminergic pathways in mediating responses to a specific stress model (hemorrhage) will also be evaluated. 3. Gonadal steroid effects on the magnocellular system. We have described pronounced and selective effects of manipulation of gonadal hormone status on the expression of coexisting peptides in magnocellular neurosecretory neurons of female rats. Systemic steroid replacement studies will be carried out in gonadectomized male rats to evaluate the generality and steroid specificity of the effect. Combined retrograde-transport -immunohistochemical methods will be used to determine whether the effect is specific to magnocellular neurons. |
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1985 — 2003 | Sawchenko, Paul E. | 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. |
Pathways Integrating Stress and Cardiovascular Responses @ Salk Institute For Biological Studies The proposed studies are designed to clarify the anatomic organization and transmitter specificity of central neural pathways subserving complementary endocrine and autonomic controls of pituitary-adrenal and cardiovascular responses to stress. Three neuropeptides synthesized by hypothalamic effector neurons, oxytocin (OT), vasopressin (AVP) and corticotropin-releasing factor (CRF), play critical roles in achieving integrated stress and cardiovascular responses. The efferent organization and visceral afferent distribution that provides for coordinated responses remain unclear. Various combinations of axonal transport and immunohistochemical methods will be used at the light and electron microscopic (EM) levels to address that following issues: 1. Peptide Interactions in Effector Neuron Pools. Anterograde tracing (PHA-L) and immunocytochemical methods will be used at the light and EM levels in normal and challenged rats to clarify the route(s) and mechanisms by which OT and AVP are delivered to the hypophyseal portal vasculature. A combined anterograde transport and immunohistochemical method will be used to chart the distribution of CRF-, AVP- and OT-immunoreactive (IR) components of hypothalamic projections to medullary autonomic effector neuron pools. 2. Differentiated Pathways Mediating Visceral Afferent Control. The visceral afferent control of neurosecretory cell groups expressing CRF, OT or AVP is gated initially through the nucleus of the solitary tract (NTS), and may involve catecholaminergic relays in the ventrolateral medulla. To determine the extent to which pathways influencing each peptidergic cell type are anatomically and biochemically differentiated, we will: (a). Chart the distribution of adrenergic projections to the PVH from each of three contributing medullary cell groups, (b). Determine the extent to which noradrenergic projections from the Al catecholamine cell group interact preferentially with magnocellular AVP neurons, (c). Determine the extent to which substance P, a potent modifier of AVP secretion, is contained within the Al projection, (d). Clarify the distributional specificity of recently discovered projections from the NTS that contain somatostatin and FSH-releasing protein, and appear to target OT neurons preferentially, and (e). Determine the organization of projections from the NTS to ventrolateral medullary catecholamine cell groups that project in turn to neurosecretory AVP- or CRF-IR cell groups. This work will provide basic information on a system that is intimately involved in the protection of the organism from stress and the maintenance of cardiovascular homeostasis. |
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1995 — 2014 | Sawchenko, Paul E. | 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. |
Anatomy of Neuroendocrine Peptide Pathways in Brain @ Salk Institute For Biological Studies The corticotropin-releasing factor (CRF) family of signaling molecules comprises four ligands (CRF, and urocortins (Ucns) 1-3), two receptors (CRFR1 and -R2) and a binding protein (CRFBP). This family is thought to play critical and interactive roles in the integration of endocrine, autonomic and behavioral responses to stress. An interconnected network of brain structures, termed the central autonomic system (CAS), harbors sensitive sites of stress-related CRF/Ucn action, but its components are generally lacking or impoverished in relevant ligand and/or receptor expression. Our goal is to clarify the functional anatomical organization that provides for generalized stress-induced CAS activation, by ascertaining the disposition and role of specific signaling molecules in specific locations that provide for recruitment of this circuitry in a range of challenge paradigms. Immunolocalization methods will be used at the light and electron microscopic levels to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. We will work with other components of the program to pursue evidence of a novel CRFR enriched in CAS, and if successful, determine its distribution and role in CAS circuitry. Histochemical and anatomical methods will be used to identify molecular targets and sites within the CAS at which CRFR1 and R2 mechanisms interact to sculpt stress responses, and to identify the underlying circuitry. Pharmacologic manipulations in genetically manipulated mouse models will be used to pursue indications of an unexpected role for the CRFBP in signaling in the CAS. Anatomical and functional studies will seek to provide a context for a newly discovered soluble CRFR2 variant. Finally, we will explore a range of possible explanations for the failure of recently discovered CRFR2-selective ligands, Ucn 2 and 3, to activate sites of cognate receptor expression. We will compare the extent to which Ucn 1, 2 and 3-expressing cell groups may be differentially responsive to a range of challenge paradigms, and employ null mutant lines to probe the roles of each peptide system in CAS responses to stress. The CMS systems under scrutiny here play essential physiologic roles in stress adaptation, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age-related deficits in learning and memory, and have been implicated in the etiology of a range of affective disorders, including anorexia nervosa and major depression. |
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1998 — 2002 | Sawchenko, Paul E. | 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. |
Cns Circuits Mediating Visceromotor Responses to Stress @ Salk Institute For Biological Studies Alterations in the expression of genes encoding hypothalamic neuroendocrine and autonomic effector peptides, and certain immediate- early gene markers of neuronal activation, will be followed, in situ, in response to various combinations of stress, central ablations, pharmacological manipulations, or perturbations in the steroid hormone environment, in order to clarify the neural circuits and mechanisms through which categorically different stressors come to elicit integrated and appropriately adaptive hypothalamic responses. An initial series of experiments will explore the mechanisms through the immune system mediator, interleukin-1 (IL-1), exerts its powerful stimulatory influence on stress-related hypothalamic mechanisms. Previous work supports the hypothesis that paracrine effects of prostaglandin E2 released from perivascular cells in the medulla as a consequence of IL-1 stimulation, and acting on a prostanoid receptor or near local catecholaminergic neurons that project to the hypothalamus, underlies the stimulatory effects of increased circulating IL-1 on stress-related hypothalamic effector neurons. This will be tested by determining whether the requisite molecules are expressed in the medulla, and by assessing whether medullary administration of. prostanoid agonists can mimic, and synthesis inhibitors block, IL-1 effects at the level of the hypothalamus. The specific involvement of medullary catecholaminergic neurons will be probed by assessing the ability of neurotoxin lesions at the level of the brainstem or delivery of adrenoceptor antagonists at the level of the hypothalamus to block hypothalamic responses to a systemic IL-1 challenge. The generality of the mechanism will be explored by determining whether disruption of ascending aminergic projections mitigates hypothalamic responses to more strenuous immune insults. A second major goal will be to employ an IEG- guided ablation strategy to identify the pathways through which ostensibly more complex, emotional or neurogenic, stress paradigms come to invoke integrated hypothalamic responses and the manner in which hypothalamic output may be modified as a consequence of repeated exposure to emotional stress. A final set of experiments will seek to characterize the neurotransmitter systems and receptor mechanisms mediating transcriptional activation of genes encoding peptides that govern pituitary-adrenal responses to stress, and the manner in which they are modulated tonically and phasically by the steroid hormone environment. The neural and neuroendocrine systems under scrutiny here play essential physiologic roles, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age- related deficits in learning and memory, and have been implicated in the etiology of affective disorders, including anorexia nervosa and major depression. |
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2003 — 2014 | Sawchenko, Paul E. | 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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Functional Anatomy of Neuroimmune Interactions @ Salk Institute For Biological Studies DESCRIPTION (provided by applicant): Cytokines, such as interleukin-1 (IL-1), released from activated immune cells during sickness or injury act on the brain to stimulate the hypothalamo-pituitary-adrenal (HPA) axis. A suggested model for this effect involves paracrine actions of prostaglandin E2 (PGE2), released from local perivascular cells as a result of IL-1 binding on brainstem catecholamine neurons that project to the hypothalamus for the initiation of HPA responses. Four sets of experiments will test this model, and advance the broader goal of clarifying the circuits and mechanism underlying immune-to-brain communication. First, to evaluate a posited interaction between endothelial and perivascular cells in transducing blood-borne cytokine signals and initiating PGE2 synthesis, the sensitivity of the two cell types in expressing inducible cyclooxygenase (COX-2) and other markers of immune activation will be compared in rats and mice over a range of IL-1 and endotoxin treatments, and the cell-specific expression of potential mediators will be examined. Knockout mice will be used to assess the roles of select genes in COX-2 induction and resultant HPA responses. Transcriptional profiling of endothelial and perivascular cells isolated from immune-stimulated mice will evaluate suspected participants in this interaction and identify novel ones. Second, a liposome-mediated targeting approach will be used to selectively destroy brain macrophages, including perivascular cells. The impact of this on HPA and other acute phase endpoints, and the CNS circuitry that mediates them, will be determined using Fos-based functional anatomical assays. Third, anatomical tracing combined with PGE2 receptor localization will identify receptor mechanisms and cell groups that participate in PGE2-mediated HPA activation. Local microinjections of subtype-selective drugs will assess the involvement of specific receptors in brainstem and other implicated sites of action. Finally, because disruption of catecholamine inputs to hypothalamus only partially mitigates endotoxin-induced HPA activation, combined lesioning, tracing and Fos-based methods will be used to identify additional candidate mediators of endotoxin effects on hypothalamus, and specify the conditions under which they are called into play. Glucocorticoid mediators of the HPA axis exert potent immunosuppressive and anti-inflammatory effects. Disruption of this restraining influence on immune function has been implicated in the genesis of autoimmune disease in animal models and in man. |
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2004 — 2007 | Sawchenko, Paul E. | 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. |
Mechanisms of Emotional Stress Effects On Hypothalamus @ Salk Institute For Biological Studies DESCRIPTION (provided by applicant): The paraventricular nucleus of the hypothalamus (PVH) is a pivotal structure in organizing adaptive responses to emotional stress, largely by virtue of its indispensable role in activating pituitary-adrenal (glucocorticoid) responses. Four sets of experiments are proposed to clarify the circuits and cellular mechanisms that mediate PVH responses to acute emotional stress, and how these come to be modified by repeated stress exposure. First, an immediate-early gene-guided ablation strategy will test the hypothesis that PVH responses to an acute emotional stress, footshock, are mediated via spinal nociceptive pathways that access the forebrain via the thalamus. A classical conditioning paradigm will be used to determine whether and how the afferent mediation of PVH recruitment by acute footshock may be transferred to pathways subserving a different sensory modality. Second, we will test the hypothesis that catecholamine inputs modulate PVH responses to acute emotional stress by reinforcing a primary drive initiated by other systems. The functional organization of local inhibitory inputs to PVH will be characterized by assessing stress and steroidal influences on identified sources of GABAergic afferents. We will attempt to establish a method for selective GABAergic denervation of PVH, to allow the role of this innervation to be assessed directly. Immunotoxin ablations will be used to [pursue] preliminary indications of an involvement of the orexin peptide system in emotional stress effects on PVH. Third, transcriptional profiling of microdissected PVH subregions will be carried out to test the hypothesis that intrinsic mechanisms are involved in habituation of PVH response to repeated emotional stress. Animals with controlled glucocorticoid levels will be used to determine how and where the hormone interacts with afferent circuitry to effect habituation. Finally, to begin to relate circuitry to cellular mechanisms, pharmacologic methods will be used to assess the role of adrenergic neurotransmission in acute stress effects on the transcription of genes encoding peptides that interact to govern pituitary-adrenal output. Lentiviral vector-mediated gene transfer will be used to evaluate the role in this context of a key transcription factor, the cyclic AMP response element-binding protein. Glucocorticoid products of the pituitary-adrenal system facilitate coping with acute emergencies, but sustained elevations in hormone levels, as seen in chronic emotional stress, is a contributing or exacerbating factor in diverse systemic, psychiatric and even neurodegenerative disorders. A fuller basic understanding of circuits and mechanisms underlying these adaptations will promote more effective management of stress related disease. |
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2008 — 2012 | Rissman, Robert A Sawchenko, Paul E. |
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. |
Stress and Crf Signaling in Alzheimer?S Disease Pathogenesis @ Salk Institute For Biological Studies DESCRIPTION (provided by applicant): Stress is implicated as a contributing factor in age-related neurodegenerative disorders such as Alzheimer's Disease (AD), which is defined by the accumulation of plaques composed of ¿-amyloid (A¿) and neurofibrillary tangles consisting of hyperphosphorylated forms of the cytoskeletal protein, tau. The means by which stress contributes to these AD hallmarks remain to be elucidated. We have found that acute exposure to an emotional stressor (physical restraint) elicits robust increases in tau phosphorylation (tau-P) in mouse hippocampus, a pivotal structure in learning and memory. We fail to implicate stress-induced glucocorticoid secretion in this respect, but find the response is abolished by disruption of signaling via the type 1 corticotropin-releasing factor receptor (CRFR1) and exaggerated in CRFR2-deficient mice. Moreover, while acute restraint-induced increments in hippocampal tau-P were short-lived, repeated daily stress sessions (14 days) led to cumulative increases in tau-P and its sequestration in insoluble, pre-pathogenic form. Five aims employing a range of biochemical, histochemical/neuroanatomical and behavioral assays are proposed to further explore the role of stress and the CRF signaling system in mechanisms of AD pathogenesis. First, we will determine whether acute restraint-induced tau-P generalizes to other brain regions afflicted in AD, other stressors that differ in potency and kind, and probe the biochemical mechanisms underlying the response. Second, to define the underlying circuitry, we will characterize sites of stress-induced tau-P (and cellular activation) using transgenic mice that report CRFR expression, use combined retrograde tracing and histochemical methods to identify sources of CRF ligand-containing inputs to hippocampus, and then test experimentally the involvement of implicated neural pathways. Third, we will characterize the effects of repeated exposure to emotional stress on tau-P and A¿ production, and explore their mechanisms and CRFR-dependence. Immunoelectron microscopy will be used to pursue preliminary evidence that repeated stress results in the formation of pre-pathogenic tau aggregates. Fourth, we will assess the ability of stress exposure over a significant portion of lifespan to modulate histochemical, biochemical and behavioral indices of tau and A¿ pathogenesis in a murine model of AD, as well as in normal aging, and determine the CRFR-dependence of observed effects. Finally, we will take advantage of a unique repository of brain material from human AD patients thoroughly characterized antemortem on indices of stress sensitivity and cognitive impairment to determine how the expression of CRF signaling molecules is altered in AD, and the extent to which such alterations may correlate with behavioral measures. The results are expected to clarify (1) the capacity of emotional stress exposure to promulgate AD- related tau and A¿ pathogenesis, (2) the neural circuitry and biochemical mechanisms underlying such effects, and (3) the extent to which they are mediated/modulated by signaling through CRFRs, which may well prove to warrant consideration as targets for therapeutic intervention in AD. PUBLIC HEALTH RELEVANCE Alzheimer's Disease is a progressive, age-related neurodegenerative disorder affecting memory and other higher brain functions, which currently afflicts roughly five million Americans. This project builds on our recent finding that a key biochemical process involved in Alzheimer's Disease can be stimulated by single or repeated exposures to stresses of the kind encountered in everyday life, and that blocking a particular neurotransmitter system in the brain can eliminate this potentially deleterious effect of stress. In deepening understanding of the brain circuits and mechanisms underlying these effects, the proposed experiments will evaluate a legitimate candidate target for the development of drugs that may slow or prevent the progression of Alzheimer's Disease. |
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2011 — 2015 | Sawchenko, Paul E. | P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Project 2 - Salk Institute For Biological Studies Ninds Center Core Grant @ Salk Institute For Biological Studies Our aim is to establish for NINDS-funded investigators an imaging core for comprehensive microscopy that will provide a coherent analytical bridge between TEM and advanced fluorescence microscopy techniques (such as confocal and two-photon imaging). Funding through the Neuroscience Center will support this effort by providing personnel with technical expertise, including a dedicated EM technician, to assist NINDS-funded investigators with their imaging needs and importantly to prepare samples for scanning and to operate the newly acquired TEM. A mechanism does not presently exist to make available to investigators the highly specialized skills in EM sample preparation, labeling, thin sectioning and analysis, that would significantly enhance many of their current and future NINDS-funded research projects by extending their investigation to the ultrastructural level. This new resource will be housed within the Waitt Advanced Biophotonics Center (WABC) at the Salk Institute. The WABC is a newly established interdisciplinary research hub within the Salk Institute whose mandate is to apply cutting-edge imaging methods to study problems of critical biological significance. The WABC occupies -2,000 sq. ft. of newly renovated laboratory and office space and provides through a recharge basis, technical and logistical access to a range of imaging, support and analytic services, as well as computational resources that support digital image analysis, including workstations, printers and a high-volume data storage capacity. |
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