Metal Toxicant Effects-Small Heat-Shock Protein Function

金属毒性作用-小热休克蛋白功能

• 批准号: 6637175
• 负责人: Michael John Welsh
• 金额: $ 102.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637175
• 关键词: heat shock proteins; metal poisoning; pathologic process; protein structure function; toxicology

Human populations in many areas of the world are exposed to several toxic metals because they occur naturally, are in food sources, or result from industrial activities. Knowledge is scare concerning mechanisms by which low exposures may cause subtle but nonetheless harmful effects on human physiology. Even less is known about the interactive effects of toxic metals. It is well known that cells mount the stress of heat-shock response when exposed to many toxicants including to toxic metals arsenic, cadmium and mercury. It is also well known that the stress response can protect cells from the effects of toxicants. Including in the events comprising cellular stress response are increased expression, phosphorylation of HSP27 , and other sHSPs, they protect themselves as individual cells and become more likely to survive the toxic insult. We hypothesize that tissue function, which depends on functional coordination of many individual cells, is altered because sHSPs tissue function, which depends on functional coordination of many individual cells, is altered because sHSPs- dependent cell functions required for tissue integrity and function have been altered as a result of increases in amounts and phosphorylation of sHSPs. Within the context of this overall hypothesis, the four individual projects of this Program Project will investigate how the toxic metals cadmium, mercury and/or arsenic affect tissue-specific functions of kidney and muscle that involve participation of hsp27, and other sHSPs and hsp27-binding proteins. Project 1 will investigate toxic metal effects on sHSPs and differentiation, structure and function of axial and cardiac muscle in embryonic development. Project 2 will study toxic metal effects on regulation of the cell cytoskeleton and morphology of kidney podocytes to learn about toxicant-induced nephrotic syndrome. Project 2 will investigate toxic metal effects on HSP27 function in kidney tubular epithelium, and Project 4 will focus on a newly discovered sHSP, HSP22, and the association of HSP22 with other sHSPs in muscle and how metal affects sHSPs and their molecular interactions in muscle. In addition to research projects, an administrative core, and two research cores, the Molecular Reagents Core and the Molecular Imaging Core will provide important resources to all the projects. It is expected that these studies will contribute significantly to our understanding of sublethal effects of toxic metals (either singly or in combinations) and the function of sHSPs in muscle and kidney.

世界许多地区的人口都接触到多种有毒金属，因为它们是天然存在的、存在于食物来源中或工业活动产生的。关于低暴露可能对人体生理机能造成微妙但有害的影响的机制的知识令人恐惧。人们对有毒金属的相互作用的影响知之甚少。众所周知，当细胞暴露于许多有毒物质（包括有毒金属砷、镉和汞）时，会产生热休克反应的应激。众所周知，应激反应可以保护细胞免受毒物的影响。包括在包括细胞应激反应在内的事件中，HSP27 和其他 sHSP 的表达增加、磷酸化，它们作为个体细胞保护自身，并且更有可能在毒性损伤中存活下来。我们假设组织功能（取决于许多单个细胞的功能协调）发生了改变，因为 sHSP 组织功能（取决于许多单个细胞的功能协调）发生了改变，因为组织完整性和功能所需的 sHSP 依赖性细胞功能已经改变。由于 sHSP 数量和磷酸化的增加。在这一总体假设的背景下，该计划项目的四个单独项目将研究有毒金属镉、汞和/或砷如何影响涉及 hsp27 和其他 sHSP 和 hsp27 参与的肾脏和肌肉的组织特异性功能。结合蛋白。项目 1 将研究有毒金属对 sHSP 以及胚胎发育中轴肌和心肌的分化、结构和功能的影响。项目2将研究有毒金属对细胞骨架和肾足细胞形态调节的影响，以了解毒物诱发的肾病综合征。项目 2 将研究有毒金属对肾小管上皮中 HSP27 功能的影响，项目 4 将重点研究新发现的 sHSP、HSP22，以及 HSP22 与肌肉中其他 sHSP 的关联，以及金属如何影响 sHSP 及其在肌肉中的分子相互作用。除了研究项目外，一个行政核心和两个研究核心、分子试剂核心和分子成像核心将为所有项目提供重要资源。预计这些研究将极大地有助于我们了解有毒金属（单独或组合）的亚致死效应以及 sHSP 在肌肉和肾脏中的功能。