The applicant plans a career as a physician-scientist in a University Medical Center. This training program involves applying state of the art research techniques to study the pathophysiology of hyponatremia in an animal model of liver disease. Hyponatremia is the most frequently occurring clinical electrolyte disorder. Problem: Hepatic cirrhosis is a chronic, progressive disease that is associated with ascites and hyponatremia. Increased circulating levels of the antidiuretic hormone, vasopressin, contribute to the development of both ascites and hyponatremia. Although it has been known for some time that centrally mediated vasopressin release contributes to the pathophysiology of cirrhosis, the pathways and mechanisms responsible have not been determined. Purpose: The goal of these studies is to determine the CNS mechanisms responsible for increased vasopressin release during cirrhosis using a rat model of obstructive cirrhosis (bile duct ligation or BDL).
Specific Aims : 1: Test the role of renin-angiotensin system in supporting the chronic activation of vasopressin neurons in bile duct ligated rats. 2: Test the hypothesis that increased expression of ?FosB produces cellular adaptations that contribute to increased excitability of vasopressin releasing neurons. Methods: The studies will employ immunocytochemistry in combination with retrograde track tracing and immunofluorescence, metabolism cage studies to measure urine and sodium excretion, chronic blood pressure and heart rate recording with radio telemetry, adeno- associated viral mediated knock down studies, patch clamp electrophysiology in brain slices, and western blot and RT-PCR analysis from brain punch samples to test these hypotheses.
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.
|Walch, Joseph D; Nedungadi, T Prashant; Cunningham, J Thomas (2014) ANG II receptor subtype 1a gene knockdown in the subfornical organ prevents increased drinking behavior in bile duct-ligated rats. Am J Physiol Regul Integr Comp Physiol 307:R597-607|
|Walch, Joseph D; Carreño, Flávia Regina; Cunningham, J Thomas (2013) Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats. Exp Physiol 98:922-33|
|Cunningham, J Thomas; Nedungadi, Thekkethil Prashant; Walch, Joseph D et al. (2012) ?FosB in the supraoptic nucleus contributes to hyponatremia in rats with cirrhosis. Am J Physiol Regul Integr Comp Physiol 303:R177-85|
|Nedungadi, T P; Carreno, F R; Walch, J D et al. (2012) Region-specific changes in transient receptor potential vanilloid channel expression in the vasopressin magnocellular system in hepatic cirrhosis-induced hyponatraemia. J Neuroendocrinol 24:642-52|
|Carreno, F R; Walch, J D; Dutta, M et al. (2011) Brain-derived neurotrophic factor-tyrosine kinase B pathway mediates NMDA receptor NR2B subunit phosphorylation in the supraoptic nuclei following progressive dehydration. J Neuroendocrinol 23:894-905|