Circadian Clock and Beta Cell Stress Adaptation

昼夜节律时钟和β细胞应激适应

• 批准号: 8629855
• 负责人: Vijay K Yechoor
• 金额: $ 34.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629855
• 关键词: Ablation; Address; Apoptotic; Beta Cell; Biological Preservation; Cell physiology; Cells; Cellular Stress; Circadian Rhythms; Coupling; Data; Diabetes Mellitus; Diet; Dose; Failure; Fasting; Functional disorder; Gene Targeting; Genes; Genetic; Glucose; Goals; Homeostasis; Human; Impairment; Insulin; Intervention; Knockout Mice; Knowledge; Lead; Life Style; Ligands; Light; Link; Mediating; Metabolic; Metabolic syndrome; Modeling; Molecular; Molecular Target; Mus; Nutrient; Obese Mice; Pathogenesis; Pathway interactions; Periodicity; Peripheral; Phase; Phenocopy; Physiological; Plasma; Prevention; Process; Production; Proteins; Regimen; Regulation; Role; Secondary to; Signal Transduction; Stimulus; Stress; Stress Tests; Tamoxifen; Testing; Transcriptional Regulation; Up-Regulation; arm; biological adaptation to stress; circadian pacemaker; combat; diabetic; diabetic patient; endoplasmic reticulum stress; feeding; in vivo; insight; insulin secretion; islet; loss of function; mitochondrial dysfunction; novel; prevent; public health relevance; research study; response; shift work; simulation; transcription factor

DESCRIPTION (provided by applicant): Circadian disruption, the bane of modern lifestyle, has been strongly associated with diabetes and metabolic syndrome. Recent human studies also implicate b-cell dysfunction as a significant component of the metabolic abnormalities. It is, therefore, imperative to understand the interaction between the circadian clock and regulation of ?-cell function for the preservation of insulin secretion to prevent diabetes. We have shown previously that genetic disruption of the circadian clock, by deletion of Bmal1, a non-redundant core clock gene, in mice, leads to ?-cell failure and diabetes, secondary to impaired glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion (GSIS). However, whether the intrinsic ?-cell clock is required for adaptive stress responses in ?-cells is unknown. In preliminary studies, we demonstrate that central clock disruption induced by shift work simulation, phenocopies genetic disruption of Bmal1 in ¿-cells in inducing Unfolded Protein Response (UPR), upregulation of the pro-apoptotic gene CHOP, suggestive of irremediable ER stress in ¿-cells, and is accompanied by impaired GSIS. Importantly, mice with a deletion of Bmal1 in ¿-cells become diabetic due to ¿-cell failure. Surprisingly, deletion of Rev-erb¿, a negative regulator of clock function and a Bmal1 target gene, leads to similar induction of unfolded protein response (UPR) in ¿-cells. We also show that ATF4, a key transcription factor involved in UPR, displays circadian rhythmicity in expression and is a direct transcriptional target of Bmal1. We, hence, hypothesized that intrinsic ?-cell clock regulators, Bmal1 and Rev-erb¿, coordinate the adaptive UPR pathway, through transcriptional control of its key components, to mitigate ER stress. The broad goal is to delineate key circadian clock-regulated pathways in ER stress-induced ¿-cell dysfunction through genetic, environmental and pharmacological modulation of the molecular clock. We will specifically 1. Test if circadian disruption is sufficient to induce ER stress and ¿-cell failure b dissecting the differential role of the central and peripheral clocks on ER stress and ¿-cell function. We will also determine the cell-autonomous role of the molecular clock in ER stress in ¿-cells 2. Define the transcriptional targets of Bmal1 and Rev-erb¿ in UPR and ER stress in ?-cells and 3. Test if the circadian clock regulates ER stress adaptive responses and insulin secretory response in human islets. We will also test if pharmacological modulation of the molecular clock can rescue adaptive stress signaling in diabetic patient islets. Collectively, the proposed studies will critically address how the molecular clock regulates ER stress and ¿-cell homeostasis and will lead to novel insights into circadian clock regulated adaptive stress pathways in ¿-cells. We envision that the results from this study will lead to discovery of targeted therapies to modulate circadian clock function for the preservation of ¿-cell function in combating diabetes.

描述（由申请人提供）：昼夜节律紊乱是现代生活方式的祸根，与糖尿病和代谢综合征密切相关。最近的人体研究也暗示b细胞功能障碍是代谢异常的重要组成部分。它是什么,