The long-term goal for this project is to determine in urogenital epithelia the cellular and regulatory pathways for bi-directional solute and fluid transport to provide a basis for better understanding urogenital diseases. Segments of the collecting duct (CD; to be studied by Dr. Wallace) and distal ductus deferens (dDD; to be studied by Dr. Schultz) have multiple cell types, suggesting the existence of cell-specific transport processes. 1) Our evidence suggests that the CD actively secretes C1- and that dDD secretes HCO3- by a Na+-dependent mechanism. Both of these observations provide a paradigm shift from current views regarding these portions of the urogenital ducts. 2) Evidence suggests that both CD and dDD have distinct mechanisms for cation absorption that have not yet been identified. 3) CD and dDD respond to distinct neurohumoral modulators, indicating that these epithelia have intrinsic capacities for regulated ion transport. Disease states result from errant regulation of these processes; e.g., net NaC1 and fluid secretion in the CD may be associated with autosomal dominant polycystic kidney disease (ADPKD) and errant Na + absorption or HCO3- secretion within the dDD are thought to contribute to infertility. The cellular and molecular basis of these observations remains to be determined. Modem cytochemical, electro-physiological, biochemical and molecular techniques will be employed to study native epithelium along with primary cell cultures to delineate the mechanisms and signaling pathways that contribute to tissue function. Our hypotheses regarding the roles of distinct cell types and transport processes will be tested by addressing the following specific aims.
Aim 1. To identify key transport mechanisms within specific cell types that support anion and fluid secretion.
Aim 2. To identify key transport mechanisms within specific cell types that support cation and fluid absorption.
Aim 3. To identify key extracellular factors that regulate hi-directional transport and their cellular modes of action. Results from these studies will lead to an increased understanding of renal and male reproductive tract function and will ultimately benefit the medical community by providing rational bases for therapeutic interventions.
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