FUNCTION OF MXI2/P38 IN STRESS SIGNALING AND ISCHEMIA

MXI2/P38 在应激信号传导和缺血中的功能

• 批准号: 6381528
• 负责人: ANTONIS S ZERVOS
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381528
• 关键词: biological signal transduction; laboratory rat; molecular cloning; phosphorylation; protein kinase; protein localization; protein metabolism; protein structure function; renal ischemia /hypoxia; renal tubule; stress; tissue /cell culture; yeast two hybrid system

DESCRIPTION(Adapted from Investigator's Abstract): The cells of an organism are continually exposed to adverse environmental conditions including extreme temperatures, osmotic pressure, toxic chemicals, and UV radiation. Viral, bacterial, and parasitic infections can also induce cellular stress. Currently, the mammalian stress-signaling pathway is poorly understood. It consists of several protein networks that extend from the plasma membrane to the cell nucleus. There are receptors that "sense" adverse conditions then activate cascades of signaling molecules to initiate the cellular stress response. This response usually protects the cells and assists in their recovery, but can also cause apoptosis in order to remove damaged or transformed cells. Very few components of the stress-signaling pathway have been characterized thus far. Known components are members of very diverse families or proteins, including membrane receptors, kinases, proteases, and transcription factors. The applicants studies on stress-signaling are focused on the function of a stress-activated kinase, Mxi2. Mxi2 is an alternative spliced form of p38 stress-activated kinase, isolated as a Max-interacting protein and expressed exclusively in the kidney. p38 is activated in response to a number of stress signals including osmotic shock, UV irradiation, polysaccharides, and several cytokines (TGF-a, IL-1), and others). P38 is also the target of a number of anti- inflammatory drugs and has a role both in ischemia and septic shock. It is the aim of the proposal to use both genetic and biochemical approaches to study the regulation of Mxi2 by stress and its function in cell recovery or apoptosis, especially in kidney after ischemia. These studies will help define the role of Mxi2 in stress-signaling, distinct from that of p38. They will also characterize the molecular events that follow kidney ischemia and provide insight into the determinants of recovery from acute renal failure.

描述（改编自研究者摘要）：生物体的细胞持续暴露于不利的环境条件，包括极端温度、渗透压、有毒化学物质和紫外线辐射。病毒、细菌和寄生虫感染也可诱导细胞应激。目前，对哺乳动物的应激信号通路知之甚少。它由从质膜延伸到细胞核的几个蛋白质网络组成。有一些受体可以“感知”不利条件，然后激活信号分子的级联反应，启动细胞的应激反应。这种反应通常保护细胞并帮助它们恢复，但也可能导致细胞凋亡，以去除受损或转化的细胞。到目前为止，压力信号通路的组成部分很少。已知的组分是非常不同的家族或蛋白质的成员，包括膜受体、激酶、蛋白酶和转录因子。申请人对应激信号传导的研究集中在应激活化激酶Mxi 2的功能上。Mxi 2是p38应激激活激酶的选择性剪接形式，作为Max相互作用蛋白分离并仅在肾脏中表达。p38响应于许多应激信号而被激活，包括渗透压休克、UV照射、多糖和几种细胞因子（TGF-α、IL-1等）。P38也是许多抗炎药物的靶点，并且在缺血和败血性休克中均起作用。该提案的目的是使用遗传和生物化学方法来研究应激对Mxi 2的调节及其在细胞恢复或凋亡中的功能，特别是在缺血后的肾脏中。这些研究将有助于确定Mxi 2在压力信号传导中的作用，与p38不同。他们还将描述肾缺血后的分子事件，并提供对急性肾功能衰竭恢复决定因素的深入了解。