Metal Toxicant Effects-Small Heat-Shock Protein Function

世界上许多地区的人口都接触到几种有毒金属，因为它们是自然产生的，存在于食物来源中，或来自工业活动。知识是关于低暴露可能对人体生理造成微妙但仍然有害的影响的机制。对有毒金属的相互作用所知甚少。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，细胞会产生热休克反应的压力。众所周知，应激反应可以保护细胞免受毒物的影响。包括在细胞应激反应的事件中，HSP27和其他sHSPs的表达增加，磷酸化，它们作为单个细胞保护自己，并更有可能在毒性损伤中存活下来。我们假设，依赖于许多单个细胞的功能协调的组织功能被改变，是因为依赖于许多单个细胞的功能协调的sHSPs的组织功能被改变，因为sHSPs的数量和磷酸化的增加改变了组织完整性和功能所需的sHSPs依赖的细胞功能。在这一总体假设的背景下，本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、其他sHSPs和hsp27结合蛋白参与的肾脏和肌肉的组织特异性功能。项目1将研究有毒金属对sHSPs和胚胎发育中轴肌和心肌分化、结构和功能的影响。项目2将研究有毒金属对肾足细胞细胞骨架和形态的调控作用，以了解毒物性肾病综合征。项目2将研究有毒金属对肾小管上皮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，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。预计这些研究将有助于我们理解有毒金属（单独或联合）的亚致死效应以及sHSPs在肌肉和肾脏中的功能。

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.