Metal Toxicant Effects-Small Heat-Shock Protein Function

世界上许多地区的人口暴露于几种有毒金属，因为它们是天然存在的，存在于食物来源中，或产生于工业活动中。关于低暴露可能对人体生理造成微妙但有害影响的机制的知识很少。关于有毒金属的交互作用更是知之甚少。众所周知，当细胞暴露于多种毒物，包括有毒金属砷、镉和汞时，细胞会产生热休克反应。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中，HSP27的表达增加，HSP27的磷酸化，以及其他sHSPs，它们作为单个细胞保护自己，并变得更有可能在有毒的侮辱中幸存下来。我们假设，依赖于许多单个细胞的功能协调的组织功能发生了改变，因为依赖于许多单个细胞的功能协调的组织功能发生了变化，因为组织完整性和功能所需的依赖于sHSPs的细胞功能已经由于sHSPs的数量增加和磷酸化而发生了改变。在这一总体假设的背景下，该计划项目的四个单独项目将调查有毒金属镉、汞和/或砷如何影响肾脏和肌肉的组织特定功能，涉及HSP27以及其他sHSPs和Hsp27结合蛋白的参与。项目1将研究有毒金属对sHSPs以及胚胎发育中轴和心肌的分化、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脏足细胞形态的调节作用，以了解毒物诱导的肾病综合征。项目2将研究有毒金属对肾小管上皮细胞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sHSPs的关系，以及金属如何影响sHSPs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(单独或联合使用)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.