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: 6927270
• 负责人: Michael John Welsh
• 金额: $ 100.97万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927270
• 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，是食物来源，或来自工业活动。关于低暴露可能对人体生理造成微妙但有害影响的机制，知识很少。对有毒金属的相互作用所知更少。众所周知，当细胞暴露于包括有毒金属砷、镉和汞在内的许多有毒物质时，细胞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。在包括细胞应激反应的事件中包括增加的表达、HSP 27和其他sHSP的磷酸化，它们作为个体细胞保护自身并且变得更可能在毒性损伤中存活。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，因为依赖于许多单个细胞的功能协调的sHSP组织功能被改变，因为组织完整性和功能所需的sHSP依赖性细胞功能由于sHSP的量和磷酸化的增加而改变。在这一总体假设的背景下，本计划项目的四个单独项目将研究有毒金属镉，汞和/或砷如何影响肾脏和肌肉的组织特异性功能，这些功能涉及hsp 27和其他sHSPs和hsp 27结合蛋白的参与。项目1将研究毒性金属对胚胎发育过程中sHSPs以及中轴肌和心肌的分化、结构和功能的影响。项目二将研究有毒金属对肾脏足细胞的细胞骨架和形态的调节作用，以了解毒物诱导的肾病综合征。项目2将研究毒性金属对肾小管上皮细胞中HSP 27功能的影响，项目4将关注新发现的sHSP，HSP 22，以及HSP 22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了解有毒金属（单独或组合）的亚致死效应以及sHSPs在肌肉和肾脏中的功能。

项目成果

Sodium arsenite exposure alters cell migration, focal adhesion localization and decreases tyrosine phosphorylation of focal adhesion kinase in H9C2 myoblasts.

亚砷酸钠暴露会改变 H9C2 成肌细胞中的细胞迁移、粘着斑定位并降低粘着斑激酶的酪氨酸磷酸化。

• DOI: 10.1093/toxsci/kfi032
• 发表时间: 2005
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Yancy,ShannonL;Shelden,EricA;Gilmont,RobertR;Welsh,MichaelJ
• 通讯作者: Welsh,MichaelJ

Myopathy-associated alphaB-crystallin mutants: abnormal phosphorylation, intracellular location, and interactions with other small heat shock proteins.

肌病相关的 αB-晶状体蛋白突变体：异常磷酸化、细胞内定位以及与其他小热休克蛋白的相互作用。

• DOI: 10.1074/jbc.m703267200
• 发表时间: 2007
• 期刊: The Journal of biological chemistry
• 作者: Simon,Stephanie;Fontaine,Jean-Marc;Martin,JodyL;Sun,Xiankui;Hoppe,AdamD;Welsh,MichaelJ;Benndorf,Rainer;Vicart,Patrick
• 通讯作者: Vicart,Patrick

Conformational changes resulting from pseudophosphorylation of mammalian small heat shock proteins--a two-hybrid study.

哺乳动物小热休克蛋白的假磷酸化引起的构象变化——一项双杂交研究。

• DOI: 10.1379/csc-149r.1
• 发表时间: 2006
• 期刊: Cell stress & chaperones
• 影响因子: 3.8
• 作者: Sun,Xiankui;Welsh,MichaelJ;Benndorf,Rainer
• 通讯作者: Benndorf,Rainer