Hypoxia plays a fundamental role in many pathogenic processes. Cancer cells in solid tumors adapt to the hypoxic microenvironment and become death-resistant and highly metastatic. On the other hand, hypoxia leads to cell death and is a key determinant of tissue pathology in ischemic diseases including myocardial infaraction, stroke and acute renal failure. Our long-term goal is to understand why some cells die during hypoxia and others can adapt to the stress and survive. One of the key factors that determine the fate of hypoxic cells appears to be gene expression. While it has been shown that mammalian cells express gene (products to increase oxygen delivery and facilitate metabolic adaptation to hypoxia, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. The objective of this proposal is to examine hypoxic regulation of genes that participate in or regulate apoptotic cell death in kidney epithelium. Our hypothesis is that expression of apoptotic genes is regulated by hypoxia. Balance between the pro- and anti- apoptotic genes is crucial for cell homeostasis and plays an essential role in determining death or survival of hypoxic cells. This hypothesis is formulated based on strong preliminary findings showing hypoxic regulation of death promoting as well as death inhibitory genes. We will test the hypothesis by pursuing four specific aims: 1, examine the roles played by transcription, mRNA stabilization and protein turnover in hypoxic expression of apoptotic genes; 2, dissect the signaling pathways that mediate apoptotic gene expression under hypoxia; 3, delineate the transcriptional mechanisms responsible for hypoxic apoptotic gene expression; 4, determine the roles played by the up-regulated apoptotic genes in cell injury or adaptation during in vitro hypoxia and in vivo ischemia. The proposed research is among the first to investigate hypoxic regulation of cell death related genes and determine its role in ischemic tissue pathology. The studies will yield important information on apoptotic gene regulation. Moreover, new insights into hypoxic cell injury and adaptation are expected. Finally, completion of these studies may help design genetic and pharmacologic strategies to diminish hypoxic tissue pathology attributable to apoptotic cell death.
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