Hypoxia and the Role of HIF-1 in the Ischemic Testis

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DESCRIPTION (provided by applicant): Oxygen is essential for the survival of all aerobic organisms. Mammalian cells are extremely sensitive to changes in oxygen concentration, particularly decreases in local oxygen supply (hypoxia). Organisms rely on a number of oxygen sensing mechanisms to detect hypoxia and stimulate molecular adaptations to respond accordingly. Testicular torsion is a medical emergency creating testicular ischemia and hypoxia that can result in germ cell loss and impaired spermatogenesis. An understanding of the molecular mechanisms involved in the response to hypoxia in the testis is critically important for understanding how cellular damage occurs in the ischemic testis. Hypoxia-inducible factor-1 (HIF-1) is considered the "master regulator" of the response to hypoxia and oxygen homeostasis in many tissues. Activated by hypoxia, HIF-1 is a transcription factor that stimulates expression of genes encoding proteins involved in responses such as increased oxygen delivery, metabolic responses, and cell rescue and cell death pathways including apoptosis. HIF-1 performs critical functions in the response to hypoxia and the pathophysiology of stroke, heart attack and other forms of ischemic injury. Previous research in our laboratory has shown that HIF-1 is produced in the rat testis and rapidly stimulated by hypoxia in the ischemic testis. Our working hypothesis is that testicular HIF-1 activates anti-apoptotic as well as pro-apoptotic pathways in the ischemic testis depending on the extent and duration of hypoxia. The overall goal of the work described in this proposal is to examine potential roles of HIF-1 in the adaptive response to hypoxia in the ischemic testis and to identify HIF-1 target genes that may be involved in cell-survival and cell-death responses that occur during testis ischemia in a rat model. The specific aims of this proposal are: (1) To test the hypothesis that HIF-1 has a pro-apoptotic role in the ischemic rat testis depending on the duration and extent of oxygen debt {hypoxia through anoxia). (2) To test the hypothesis that HIF-1 contributes to cell damage in the ischemic rat testis by interacting with the tumor suppressor protein p53 under conditions of testicular hypoxia or anoxia. (3) To test the hypothesis that anti-apoptotic (Mcl-1) and pro-apoptotic (Bax, Nip3) genes are transactivation targets for HIF-1 in the ischemic testis. Knowledge gained from the proposed experiments will be relevant to understanding cellular and molecular responses to hypoxia in the ischemic testis and provide fundamental insight on the role of HIF-1 in pathophysiologic effects of hypoxia and testicular ischemic injury.