Neural Control of Vasopressin Release


Principal Investigator: J Thomas Cunningham
Abstract: DESCRIPTION (provided by applicant): Hyponatremia is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year. Inappropriate vasopressin secretion is the major cause of dilutional hyponatremia associated with liver and heart failure. Brain derived neurotrophic factor (BDNF) and its receptor TrkB are expressed by magnocellular neurosecretory cells that secrete vasopressin into circulation. Our studies will be among the first to test the role of the BDNF-TrkB signaling in the homeostatic regulation of the neurohypophyseal system and in an animal model of inappropriate vasopressin release. We propose that activation of the BDNF-TrkB system increases vasopressin release by enhancing the postsynaptic effects of NMDA receptors on vasopressin release. Specific Aim 1: will test the role of neurohypophysial BDNF-TrkB signaling on the effects of water deprivation on neurohypophyseal function and vasopressin release. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to phosphorylation of NMDA receptor subunits through Fyn kinase, a downstream member of the Src kinase family. In these experiments we will test whether BDNF-trkB mediated neuroplasticity contribute to sustained vasopressin release produced by water deprivation. Specific Aim 2: will test the hypothesis that neurohypophysial BDNF-TrkB signaling contributes to inappropriate vasopressin release in an animal model of dilutional hyponatremia. Hypothesis: BDNF-TrkB mediated changes in NMDA receptor function contribute to changes in the osmotic and non-osmotic regulation of vasopressin neurons in rats with experimental induced hepatic cirrhosis. In these experiments, the bile duct ligation model of cirrhosis-induced hyponatremia will be used to test the role of the BDNF-TrkB signaling on SON neurons in the context of inappropriate vasopressin release. Methods: The studies will employ Western blot and co-immunoprecipitation in combination with immunohistochemistry and laser capture microdissection RT-PCR, metabolism cage studies to measure urine and sodium excretion, and in vitro electrophysiology to test these hypotheses. Benefit: These experiments will address an existing gap in our understanding of neurohypophyseal function and the pathogenesis of hyponatremia. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.
Funding Period: 2000-09-15 - 2014-08-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Role of the CNS in Inappropriate Vasopressin Release Associated with Cirrhosis
    JOSEPH D WALCH; Fiscal Year: 2013
    ..PUBLIC HEALTH RELEVANCE: The results from these studies will determine the mechanisms that contribute to the pathophysiology of fluid retention in a chronic disease state that is reported to be the 5th leading cause of death in the USA. ..
    John E Hall; Fiscal Year: 2013
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  4. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  5. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  6. Role of Sphingolipids in the Pathobiology of Lung Injury
    Viswanathan Natarajan; Fiscal Year: 2013
    ..Together, this PPG addresses critical needs (insights, biomarkers, therapies) in ALI and RILI facilitating development of pharmacogenomic assays and SIP-based therapies for inflammatory lung injury. ..
  7. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
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  8. COBRE in Lipidomics and Pathobiology
    Besim Ogretmen; Fiscal Year: 2013
  9. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  10. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
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  11. Enduring Effects of Early-Life Serotonin Signaling
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  12. Amygdala Serotonin Neurotransmission and Neuropathic Pain
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    ..The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide translational strategies for pharmacotherapeutics and/or gene therapy. ..
  13. Neurocircuitry Underlying DBS Effects in OCD: A Window Into Mechanisms of Action
    Suzanne N Haber; Fiscal Year: 2013
    ..Results from these studies will also make important new contributions to our understanding of the basic mechanisms of DBS. ..
  14. Novel Mechanisms and Therapies in Heart Failure
    Howard A Rockman; Fiscal Year: 2013
    ..The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure. ..
  15. Southern California Research Center for ALPD and Cirrhosis
    Hidekazu Tsukamoto; Fiscal Year: 2013
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    Charles E Wood; Fiscal Year: 2013
    ..The results are likely to demonstrate the importance of NMDA receptor blockade as a neuroprotective strategy in late gestation fetuses and for premature infants in the NICU. ..
  17. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
    Teresa A Milner; Fiscal Year: 2013
    ..Moreover, they may provide the mechanistic basis for developing more effective therapeutic strategies for the management of post-menopausal increases in blood pressure. ..
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  21. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  22. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  23. Regulation of Liver by Nuclear Ca2+ Signaling
    Michael H Nathanson; Fiscal Year: 2013
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    HERBERT DAVID KLEBER; Fiscal Year: 2013
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    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  26. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
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  27. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..