Hypoxia and Potassium Channel Activity in T Lymphocytes

T 淋巴细胞缺氧和钾通道活性

基本信息

批准号：
6615927
负责人：
LAURA CONFORTI
金额：
$ 29.12万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在生理状况（例如高海拔）和病理状况（例如心肺疾病和癌症）中都可能遇到氧气利用率下降（缺氧）。尽管缺氧通常与多种人类疾病的不良结果相关，但参与疾病进展的不同细胞类型对氧气可用性变化做出反应的基本机制仍知之甚少。免疫细胞参与许多疾病状态，其功能影响病理的缓解或改善。各种体外研究表明，缺氧会抑制宿主免疫细胞的功能。虽然缺氧抑制 T 细胞活性的机制尚不清楚，但缺氧对其他细胞类型的下游影响已得到广泛研究。因此我们知道 K 通道活性的抑制是缺氧后发生的早期事件之一，最终导致细胞功能的变化。 Kv1.3 基因编码的 K 通道在 T 淋巴细胞中表达，控制膜电位和细胞活性。初步数据表明，天然（在人 T 淋巴细胞中）和重组 Kv1.3 通道会受到缺氧的抑制。抑制这些通道已被证明可以抑制 T 细胞活化。事实上，进一步的初步证据表明缺氧会抑制 T 淋巴细胞中的 Ca 2+ 动员和增殖。因此，我们假设缺氧对 T 细胞功能的影响部分是由缺氧抑制 Kv1.3 通道的能力介导的。拟议的研究旨在研究缺氧对 T 细胞 Kv1.3 通道活性的影响，并确定其缺氧抑制的功能意义。还将进行实验以确定介导 T 细胞中 Kv1.3 通道氧敏感性的信号通路。将结合使用电生理学、免疫学和分子生物学技术。拟议研究的结果将为缺氧免疫反应的分子基础提供新的见解，并将进一步加深我们对缺氧介导的 T 细胞功能变化的离子机制的理解。