Characterization of the role of gap junction proteins in ER stress and obesity

间隙连接蛋白在内质网应激和肥胖中作用的表征

• 批准号: 8424046
• 负责人: Amir Tirosh
• 金额: $ 15.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424046
• 关键词: Address; Adenoviruses; Adipocytes; Adipose tissue; Algorithms; Atherosclerosis; Attention; Cell Communication; Cell Line; Cells; Cellular Stress; Chemicals; Chronic; Coculture Techniques; Communication; Connexin 43; Connexins; Data; Development; Diabetes Mellitus; Diet; Diffusion; Disease; Dyes; Fatty acid glycerol esters; Functional disorder; Gap Junctions; Genetic; Heart Diseases; Hepatocyte; Homeostasis; Immune; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knock-in Mouse; Knock-out; Life; Light; Link; Lipolysis; Liver; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Molecular Weight; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Overnutrition; Pathway interactions; Physiological; Physiology; Play; Prevalence; Procedures; Protein Isoforms; Proteins; Regulation; Reporting; Research; Resistance; Resistance development; Risk; Role; Signal Transduction; Small Interfering RNA; Stress; System; Testing; Tissue Preservation; Tissue Survival; Tissues; endoplasmic reticulum stress; fasting glucose; gain of function; gap junction channel; genetic manipulation; glucose metabolism; glucose production; glucose tolerance; improved; insulin signaling; intercellular communication; loss of function; mRNA Expression; mouse model; novel; overexpression; preconditioning; prevent; promoter; protein expression; reconstitution; response; transmission process

DESCRIPTION (provided by applicant): Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. Extensive research in recent years has unraveled many cellular mechanisms in obesity, integrating metabolic signals and inflammatory pathways. Endoplasmic reticulum (ER) stress has been shown to play an important role in metabolic diseases and is linked to both metabolic and immune regulation. While the cellular mechanisms linking overnutrition to ER stress, inflammation and disruption of insulin signal transduction have been extensively studied, the adaptation at the tissue level as a network of living and communicating cells has not been explored. In recent years, it has been shown that gap junction channels play a pivotal role in tissue adaptation to stress and inflammation in various tissues and pathophysiological conditions. Gap junctions facilitate direct cytoplasmic communication between neighboring cells, allowing the transfer of small-molecular-weight molecules involved in cell signaling and metabolism and promoting tissue survival. Assessing the potential role of cell-cell communication through gap junctions in obesity and diabetes in metabolically relevant tissues such as liver and adipose tissue is the primary focus of this proposal. The overarching hypothesis of this project is that obesity-induced ER stress in liver and adipose tissue requires increased gap junction mediated cell-cell communication in order to manage stress and to maintain tissue function and whole-body metabolic homeostasis. Abnormal activation of liver and/or adipose tissue gap junctions may, therefore, represent a novel mechanism for obesity induced metabolic abnormalities. The aim of this study is to assess the potential role of the gap junction proteins (connexins [Cxs]) in the adaptation of liver and adipose tissue to ER stress, overnutrition and obesity. The regulation of connexins under these conditions will be studied, as will their potential to improve tissue dysfunction and whole-body metabolism in obesity and diabetes. A thorough understanding of the plausible role of gap junction communication in maintaining metabolic homeostasis in normal physiology and under conditions of nutrient excess is important to fully understand, and to subsequently treat, chronic metabolic diseases. PUBLIC HEALTH RELEVANCE: The mechanisms responsible for the development of resistance to the effects of insulin in obesity and diabetes are not fully understood. Our preliminary results suggest that communication of cells through gap junction channels may be important for better adaptation of liver and adipose tissue to obesity and stress conditions and for maintaining their metabolic functions. The successful completion of the proposed research will shed light on novel mechanisms for the development of metabolic abnormalities in obesity and diabetes.

描述（由申请人提供）：肥胖是世界范围内的一个主要问题，它增加了多种疾病的风险，包括糖尿病和心脏病。近年来的广泛研究揭示了肥胖的许多细胞机制，整合了代谢信号和炎症途径。内质网（ER）应激已被证明在代谢疾病中发挥重要作用，并且与代谢和免疫调节有关。虽然营养过剩与内质网应激、炎症和胰岛素信号转导破坏相关的细胞机制已被广泛研究，但组织水平作为活细胞和通讯细胞网络的适应尚未得到探索。近年来，研究表明间隙连接通道在组织适应各种组织和病理生理条件的应激和炎症方面发挥着关键作用。间隙连接促进相邻细胞之间的直接细胞质通讯，允许参与细胞信号传导和代谢的小分子量分子的转移，并促进组织存活。该提案的主要重点是评估代谢相关组织（如肝脏和脂肪组织）中通过间隙连接进行细胞间通讯在肥胖和糖尿病中的潜在作用。该项目的总体假设是，肥胖引起的肝脏和脂肪组织内质网应激需要增加间隙连接介导的细胞间通讯，以管理应激并维持组织功能和全身代谢稳态。因此，肝脏和/或脂肪组织间隙连接的异常激活可能代表肥胖引起的代谢异常的新机制。本研究的目的是评估间隙连接蛋白（连接蛋白 [Cxs]）在肝脏和脂肪组织适应内质网应激、营养过剩和肥胖方面的潜在作用。将研究这些条件下连接蛋白的调节，以及它们改善肥胖和糖尿病的组织功能障碍和全身代谢的潜力。彻底了解间隙连接通讯在正常生理和营养过剩条件下维持代谢稳态中的合理作用对于充分了解并随后治疗慢性代谢疾病非常重要。 公共卫生相关性：肥胖和糖尿病中胰岛素作用产生抵抗的机制尚不完全清楚。我们的初步结果表明，细胞通过间隙连接通道进行的通讯可能对于肝脏和脂肪组织更好地适应肥胖和应激条件以及维持其代谢功能很重要。该研究的成功完成将揭示肥胖和糖尿病代谢异常发展的新机制。