Clock genes, environmental challenges and cardiopulmonary disease

描述（由申请人提供）：本申请涉及广泛的挑战领域15：转化科学和特定的挑战主题15- es -101：使用非人类模型的环境暴露对表型结果的影响。大约有860万美国人轮班工作，这与心血管和心肺疾病的风险增加有关。光污染是环境条件之一，被认为是一个贡献者轮班工人的病理增加。2007年NIEHS发布了一份关于光污染的报告；“现代社会慢性疾病的急剧增加可能与光明和黑暗模式的改变有关”。环境照明模式改变的关键生理目标之一是昼夜节律定时系统。越来越多的人认识到，倒班工人的病理增加可能是由于组织/器官内的分子昼夜节律计时系统与由于光线照射中断而改变的环境时间线索之间的不一致引起的。挑战主题应用程序中描述的项目目标将使用核心昼夜节律基因Bmal1的靶向组织特异性破坏，并控制环境光线索的操作，以确定心肺疾病进展中遗传和环境因素之间的相互作用。分析将包括使用体内遥测和超声心动图来提供系统性疾病进展的纵向数据。此外，实验将进行，将提供机械洞察使用分子，细胞和生化方法。该项目的总体假设是，在肌肉组织（心脏或光滑或骨骼）中靶向删除Bmal1将削弱动物处理光污染的能力，并将与心肺疾病的更快和更深刻的进展有关。对于这个由肌肉生物学和心肺疾病研究人员组成的团队来说，这是一个新的研究领域。他们在昼夜节律、心脏、平滑肌和骨骼肌生物学领域的专业知识和成功合作的历史将使这一高度优先的研究领域取得快速进展。在这个为期两年的项目结束时，我们有信心将获得关于心肺组织中分子钟功能与环境光挑战之间相互作用及其对疾病进展的贡献的重要新数据。大约有860万美国人轮班工作，这与心血管和心肺疾病的风险增加有关。根据NIEHS 2007年的报告，光污染是环境条件之一，被认为是轮班工人疾病增加的一个因素。本应用项目的目标是确定改变的昼夜节律基因与环境因素在心肺疾病进展中的相互作用。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 15: Translational Science and specific Challenge Topic 15-ES-101: Effects of environmental exposures on phenotypic outcomes using non-human models. Approximately 8.6 million Americans perform shift work, which is associated with increased risk of cardiovascular and cardiopulmonary diseases. Light pollution is one of the environmental conditions that is suggested to be a contributor to the increased pathologies in shift workers. In 2007 the NIEHS released a report on light pollution noting; "that the dramatic increases in chronic diseases in modern society maybe associated with the altered patterns of light and dark". One of the key physiological targets of altered patterns of environmental lighting is the circadian timing system. There is growing recognition that the increased pathologies seen in shift workers could arise from misalignment between the molecular circadian timing system within tissues/organs and the altered environmental time cue due to disrupted light exposure. The goal of the projects described in this Challenge Topic application will use targeted tissue specific disruption of a core circadian gene, Bmal1, with controlled manipulation of environmental light cues to determine the interaction between genetic and environmental factors in the progression of cardiopulmonary disease. Analyses will include use of in vivo telemetry and echocardiography to provide longitudinal data on systemic disease progression. In addition, experiments will be performed that will provide mechanistic insight using molecular, cellular and biochemical approaches. The overall hypothesis for this project is that targeted deletion of Bmal1 in muscle tissues (heart or smooth or skeletal) will weaken the animal's ability to handle light pollution and will be associated with a more rapid and profound progression to cardiopulmonary diseases. This is a novel area of research for this team of established investigators in muscle biology and cardiopulmonary disease. Their combined expertise and prior history of successful collaboration in the areas of circadian rhythms, cardiac, smooth and skeletal muscle biology will allow for rapid progression on this high priority research area. At the end of this two-year project we are confident that will have obtained significant new data regarding the interaction between the molecular clock function in cardiopulmonary tissues and environmental light challenges and their contribution to disease progression. Approximately 8.6 million Americans perform shift work, which is associated with increased risk of cardiovascular and cardiopulmonary diseases. As reported in 2007 by NIEHS, light pollution is one of the environmental conditions that is suggested to be a contributor to the increased pathologies in shift workers. The goal of the projects in this application will determine the interaction between altered circadian genes with environmental factors in the progression of cardiopulmonary disease.