PI: Fabrisia Ambrosio and Aaron Barchowsky
Co-PI: William Wagner, Antonio D’Amore, and Donna Stolz
Titles: Dysfunctional Muscle Remodeling and Regeneration in Environmental Disease
Description: Arsenic is an odorless and tasteless semi-metal that contaminates drinking water supplies from natural deposits in the earth. It is estimated that almost 3.7 million individuals in the US, and over 140 million individuals worldwide, are exposed regularly to drinking water that exceed government arsenic standards. Increasing attention has been recently paid to the declines in functional mobility resulting from chronic arsenic exposure, which we now understand to pose a significant risk for causing skeletal muscle myopathies and atrophy, impairments that are among the greatest factors contributing to declines in functional mobility and strong predictors of mortality. However, many questions of the health impacts of environmental exposures throughout life remain, including the underlying mechanisms by which exposures negatively impact the cellular microenvironment, stem cell phenotype and, ultimately, tissue maintenance and healing capacity. The objective of this proposal is to elucidate mechanisms for arsenic-stimulated alteration of transcriptional circuitries that disrupt intra- and inter-cellular communication within the niche and compromise muscle structural integrity.
We propose two specific aims to test our central hypothesis that arsenic stimulates fibroblast-mediated pathogenic matrix alterations, resulting in stem cell dysfunction and, ultimately, impaired wound repair after injury. In Specific Aim 1, we will test the hypothesis that exposure to commonly encountered levels of arsenic in drinking water promotes pathologic matrix remodeling to impair muscle stem cell function and regenerative capacity. In Specific Aim 2, we will test the hypothesis that arsenic dysregulates fibroblast activation, driving an impaired muscle stem cell function and tissue repair response after injury. Success in these aims will both increase our understanding of the pathogenesis of arsenic-induced clinical symptoms of myasthenia, and will elucidate skeletal muscle microenvironmental factors controlling stem cell declines. The long-term goal is to create prevention and/or intervention strategies to improve health outcomes of individuals living in arsenic-endemic areas.
Source: National Institute on Environmental Health Sciences