Pathogenic environmental regulation of miRNA biogenesis and function

miRNA 生物合成和功能的致病环境调控

• 批准号: 8395272
• 负责人: Kevin J Beezhold
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395272
• 关键词: Accounting; Adipocytes; Adipose tissue; Affect; Apoptosis; Arsenic; Atherosclerosis; Basic Science; Binding Proteins; Biogenesis; Blood Vessels; Brown Fat; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell physiology; Cells; Chronic; Chronic Disease; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Environmental Hazards; Environmental Impact; Environmental Pollution; Environmental Risk Factor; Etiology; Event; Exposure to; Family; Family member; Gene Expression; Genes; Health; Human; Hypertension; Impairment; Injury; Liver; Mediating; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Metabolic; Metabolic Diseases; MicroRNAs; Modeling; Molecular; Mus; Muscle Cells; Natural regeneration; Pathogenesis; Pathology; Peripheral; Phenotype; Physiological; Play; Population; Post-Transcriptional Regulation; Public Health; Regulation; Relative (related person); Reporting; Research; Risk; Role; Signal Transduction; Stem cells; Testing; Therapeutic Intervention; Tissues; Toxic Environmental Substances; Transcription Process; Translational Repression; Translations; Vascular Diseases; Vascular remodeling; adult stem cell; base; carcinogenesis; cardiac repair; drinking water; effective intervention; exposed human population; improved; member; men; novel; prevent; programs; protein expression; regenerative; response; stem; stem cell differentiation

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.

描述(由申请人提供)：人类接触环境毒物是众所周知的致病原因，低慢性接触可能会显著增加慢性病的纵向风险。许多环境毒物的致病机制仍然不明确，这限制了有效干预措施的发展，以预防环境引起的慢性疾病。低剂量接触饮用水中的三价砷As(III)是一个主要的公共卫生问题，导致许多疾病和病理，包括心血管和代谢性疾病。虽然在理解导致砷诱导疾病的致病信号事件方面取得了进展，但许多相关的机制还没有被阐明。控制miRNA的表达和作用为理解砷暴露的下游效应提供了一种很有前途的新手段；然而，关于砷如何调控miRNA的表达和影响其功能的报道很少。因此，拟议的研究将使用砷作为理想的致病环境毒物来检查对miRNA调节的表型程序的影响。为了更好地研究砷对miR-29家族(包括miR-29a、29b-1、29b-2和29c)的生物发生和致病作用的影响，我们将研究砷对miR-29家族的影响。这个miRNA家族是在几项研究的基础上选择的，这些研究表明miR-29成员在病因学、心血管疾病和代谢性疾病中的增加。我们的初步数据显示，当砷抑制脂肪细胞分化时，从染砷(100 mg/L，饮用水中2wk)的小鼠分离的白色和棕色脂肪组织以及在人类脂肪来源的间充质干细胞(HMSC)中诱导了miR-29。干细胞或祖细胞分化能力降低被认为是疾病进展的基本手段，我们将以hMSCs向脂肪细胞和心肌细胞的分化为模型来研究砷对致病miRNA调节程序的影响。研究的主要假设是砷诱导miRNAs的转录表达，并影响它们在抑制调控hMSC分化的基因程序中的功能，从而损害心脏或代谢组织的再生能力和适应性修复。这一假说将通过以下具体目标进行研究：1.确定砷诱导miR-29家族成员表达的调控机制及其功能影响。砷刺激miR-29生物发生的机制将在hMSC中进行研究，重点是损伤hMSC、脂肪细胞和心肌细胞的分化。限速步骤的分子敲除将确定砷如何诱导miR-29家族成员的表达和致病作用。Ii.检验细胞环境和环境因素影响相关miRNA功能活性的假设。重点将放在研究砷如何调节miR-29家族成员对其mRNA靶标的不同活性。将研究mRNA结合蛋白的表达和能力与它们增强或减少miRNA介导的翻译抑制的能力的关系。 与公共卫生的相关性：慢性病的环境基础是公认的公共卫生问题，但从机械上讲，人们对此知之甚少，包括接触饮用水中的砷，众所周知，这会在全球人口中造成重大的健康影响，包括心血管和新陈代谢疾病。拟议中的研究调查了暴露于砷对miRNA的影响，miRNA是新发现的小而强大的细胞调节因子，在成人干细胞库的病理反应中损害再生或 能预防疾病的适应性反应。这项研究将确定致病砷的作用机制，以及对miRNA生物发生和功能的调控机制的基本了解，以确定治疗干预或保护免受环境源性疾病影响的新靶点。