Hypoxia and Potassium Channel Activity in T Lymphocytes

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DESCRIPTION (provided by applicant): A decrease in oxygen availability (hypoxia) can be encountered both in physiological (e.g. high altitude) and pathological conditions (e.g. cardio-pulmonary diseases and cancer). Although hypoxia is usually associated with a poor outcome in several human disorders, the basic mechanisms by which the different cell types involved in the progression of the disease respond to the change in O2 availability are still poorly understood. Immune cells participate in many disease states and their functionality affects the remission or amelioration of the pathology. Various in vitro studies have indicated that hypoxia can inhibit the function of the host immune cells. While the mechanisms whereby hypoxia inhibits T cell activity are not well understood, the downstream effects of hypoxia on other cell types have been extensively studied. Thus we know that inhibition of K channel activity is one of the early events that occur following hypoxia and which eventually leads to changes in cellular function. K channels encoded by the Kv1.3 gene are expressed in T lymphocytes and control membrane potential and cell activity. Preliminary data indicate that native (in human T lymphocytes) and recombinant Kv1.3 channels are inhibited by hypoxia. Inhibition of these channels has been shown to inhibit T cell activation. Indeed, further preliminary evidence indicates that hypoxia inhibits Ca 2+ mobilization and proliferation in T lymphocytes. Therefore we hypothesize that the effect of hypoxia on T cell function is in part mediated by the ability of hypoxia to inhibit Kv1.3 channels. The proposed research aims to study the effect of hypoxia on Kv1.3 channel activity in T cells and to determine the functional implications of their hypoxic-inhibition. Experiments will be also performed to identify the signaling pathways mediating the oxygen sensitivity of Kv1.3 channels in T cells. A combination of electrophysiological, immunological and molecular biological techniques will be used. Findings from the proposed studies will provide new insights into the molecular basis of the immune response in hypoxia and will further our understanding of the ionic mechanisms of hypoxia-mediated changes in T cell function.