Pathogenic environmental regulation of miRNA biogenesis and function

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DESCRIPTION (provided by applicant): Human exposure to environmental toxicants is a well known cause of disease and low chronic exposure may contribute significantly to longitudinal risk of chronic diseases. Pathogenic mechanisms for many environmental toxicants remain poorly defined which limits development of effective interventions to protect against environmentally-derived chronic diseases. Low dose exposure to trivalent arsenic As(III) in drinking water is a major public health concern that contributes to a number of diseases and pathologies, including cardiovascular and metabolic diseases. While progress has been made in the understanding of the pathogenic signaling events contributing to arsenic-induced disease, many responsible mechanisms have not been elucidated. Control of miRNA expression and action presents a promising new means for understanding downstream effects of arsenic exposure; however, there are few reports of how arsenic regulates expression of miRNA and impacts their function. Thus the proposed studies will use arsenic as an ideal pathogenic environmental toxicant to examine impact on miRNA regulated phenotypic programs. To focus the studies, impact of arsenic on miR-29 family (including miR-29a, 29b-1, 29b-2 and 29c) biogenesis and pathogenic actions will be investigated. This miRNA family was selected based on several studies implicating increased miR-29 members in the etiology cardiovascular and metabolic diseases. Our preliminary data show induction of miR-29 in white and brown adipose tissue isolated from arsenic exposed (100 mg/L in drinking water for 2 wk) mice and in human adipose-derived mesenchymal stem cells (hMSC) as arsenic inhibited adipocyte differentiaton. Reduced stem or progenitor cell differentiation capacity is believed to be a fundamental means for disease progression and we will use the differentiation of hMSCs into adipocytes and cardiomyoctes as a model to examine arsenic effects on pathogenic miRNA regulatory programs. The overarching hypothesis investigated is that arsenic induces transcriptional expression of miRNAs and impacts their function in repressing gene programs that regulate hMSC differentiation thereby impairing regenerative capacity and adaptive repair of cardiac or metabolic tissues. This hypothesis will be studied by the following specific aims: I. Identificatio of the mechanisms regulating arsenic-induced miR-29 family member expression and its functional impact. Mechanisms of arsenic-stimulated miR-29 biogenesis will be studied in hMSC with focus on impaired hMSC, adipocyte and myocyte differentiation. Molecular knockdown of rate limiting steps will identify how arsenic induces the expression and pathogenic role of the miR-29 family members. II. To test the hypothesis that cell context and environmental factors impact the functional activity of relevant miRNA. Focus will be on investigating how arsenic regulates differential activity of miR-29 family members on their mRNA targets. The expression and ability of mRNA binding proteins will be studied in relation to their ability to enhance or reduce miRNA mediated translational inhibition. PUBLIC HEALTH RELEVANCE: The environmental basis of chronic diseases is a well recognized public health concern, but is mechanistically poorly understood, including exposure to arsenic in drinking water which is well known to cause significant health effects including cardiovascular and metabolic diseases in populations across the globe. The proposed studies investigate impact of arsenic exposure on miRNA, the newly discovered, small, yet powerful cellular regulators, in pathological responses in adult stem cell pools that impair regenerative or adaptive responsive that prevent disease. This research will identify mechanisms for pathogenic arsenic effects, as well as basic understanding of regulatory mechanisms for miRNA biogenesis and function that may identify novel targets for therapeutic intervention or protection from environmentally-derived disease.