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.
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