The primary objective of this application is to investigate the molecular characteristics of the human placental sodium-proton exchanger and the mechanisms involved in the regulation of its activity. The long-term goal of the project is to understand the physiological role of the exchanger in the placental function. The fetus depends on the placenta for its obligatory link with its mother. The human placenta is a promising tool to conduct investigations on many of the placental functions that are crucial for the growth and development of the fetus. From what is known on the properties of the sodium-proton exchanger in other cell types, there is no doubt that the exchanger is intimately involved in the regulation of the placental function. Unlike most other transport systems which perform a single task, the sodium-proton exchanger serves a variety of functions. The most important of these are the regulation of intracellular pH, the control of cell volume, and the transepithelial transport of sodium and acid equivalents. These functions are directly related to important cellular processes such as cell growth and differentiation and transfer of organic solutes across the cell membrane. The experiments proposed in the project are designed to probe the placental sodium-proton exchanger in two important areas, molecular identification and regulation. All experiments will be done with human term placentas and the exchanger activity will be analyzed in purified brush border (or basal) membrane vesicles. Identification of the exchanger will be carried out with radiolabeled affinity probes. These radiolabeled tags will be used to monitor the exchanger in the placental brush border membrane is distinct from the exchanger of the intestinal and renal brush border membranes, but is identical or similar to the exchanger in the plasma membrane of non- polarized cells. This observation is unique and important and warrants more detailed studies. Experiments are proposed to compare the pharmacological and molecular properties of the exchangers in brush border membranes isolated from kidney intestine and placenta. Regulation of the sodium-proton exchanger will be investigated, with emphasis on the involvement of protein phosphorylation and guanine nucleotide binding proteins. This project has the potential to generate new and important information on the regulation of the exchanger activity by hormones and other humoral factors that are present in the maternal and fetal circulations.
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