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.
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.
| Harfmann, Brianna D; Schroder, Elizabeth A; Kachman, Maureen T et al. (2016) Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis. Skelet Muscle 6:12 |
| Schroder, Elizabeth A; Harfmann, Brianna D; Zhang, Xiping et al. (2015) Intrinsic muscle clock is necessary for musculoskeletal health. J Physiol 593:5387-404 |
| Harfmann, Brianna D; Schroder, Elizabeth A; Esser, Karyn A (2015) Circadian rhythms, the molecular clock, and skeletal muscle. J Biol Rhythms 30:84-94 |
| Schroder, Elizabeth A; Burgess, Don E; Zhang, Xiping et al. (2015) The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization. Heart Rhythm 12:1306-14 |
| Xie, Zhongwen; Su, Wen; Liu, Shu et al. (2015) Smooth-muscle BMAL1 participates in blood pressure circadian rhythm regulation. J Clin Invest 125:324-36 |
| Schroder, Elizabeth A; Burgess, Don E; Manning, Cody L et al. (2014) Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice. Am J Physiol Heart Circ Physiol 307:H1777-85 |
| Schroder, Elizabeth A; Esser, Karyn A (2013) Circadian rhythms, skeletal muscle molecular clocks, and exercise. Exerc Sport Sci Rev 41:224-9 |
| Schroder, Elizabeth A; Lefta, Mellani; Zhang, Xiping et al. (2013) The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. Am J Physiol Cell Physiol 304:C954-65 |
| Wolff, Gretchen; Duncan, Marilyn J; Esser, Karyn A (2013) Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks. J Appl Physiol (1985) 115:373-82 |
| Lefta, Mellani; Campbell, Kenneth S; Feng, Han-Zhong et al. (2012) Development of dilated cardiomyopathy in Bmal1-deficient mice. Am J Physiol Heart Circ Physiol 303:H475-85 |
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