The overall objective of the five research proposal comprising this program project is to continue an integrated exploration into the mechanisms of vasopressin secretion and action as they relate to normal and pathophysiological states. The hyperdynamic circulatory response to pregnancy, high-output cardiac failure and cirrhosis are characterized by a primary decrease in systemic vascular resistance and vasodilation- mediated arterial underfilling. Systemic and renal hemodynamics, hormonal responses, as well as sodium and water balance including AVP- stimulated aquaporin-2 (AQP-2) water channels will be examined after normalizing the hyperdynamic circulation in these states by inhibiting nitric oxide synthase (NOS) with and without cyclooxygenase inhibition in rats. These parameters also will be examined in NOS and AQP-1 knockout mice. Small cell lung cancer is one of the most common causes of the syndrome of inappropriate AVP secretion. The signaling pathways that mediate the mitogenic actions of AVP on small cell cancer cells will be studied to determine the role of c-Jun N-terminal kinase (JNK) activation and G protein regulation of Src and Tec tyrosine kinases in this process. Studies of the signaling pathways involved in VP action on vascular smooth muscle cell differentiation will examine the regulation of smooth muscle alpha-actin (SM-alpha-actin) by JNK activation and small molecular weight G proteins and phospholipase A2. Specific transcription factors acting directly on the SM-alpha-actin promoter will be examined in this section. These studies will identify the molecular events responsible for the distinct growth patterns associated with hyperplasia, contraction and hypertrophy. The molecular pathways which enable collecting duct cells to sustain the osmotic stress of a hypertonic environment will be examined in rat inner medulla and IMCD3 cells by studying the JNKs and their upstream kinases, MMK4, MMK7, the MEKKs and small molecular weight G proteins, Rac, Cdc42 and Ras. Downstream effectors will be analyzed as mediators of kinase action with attention to heat shock proteins. Inhibitory mutants will also be used to access the physiologic significance of the pathway components. The neurohypophyseal system responsible for the central release of AVP will be examined by studying the mechanisms regulating AVP gene transcription including the role of putative regulatory elements in the promoter region of the AVP gene and specific transcription factors required for regulation AVP gene transcription in osmotic and non-osmotic stimulated states. Mechanisms of processing of the AVP precursor in normal and mutated (central diabetes insipidus) states will also be examined.
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