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

描述(申请人提供)：肥胖是世界范围内的一个主要问题，它增加了患各种疾病的风险，包括糖尿病和心脏病。近年来广泛的研究揭示了肥胖症的许多细胞机制，整合了代谢信号和炎症途径。内质网应激在代谢性疾病中起重要作用，并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中断的细胞机制已经被广泛研究，但在组织水平上作为一个活的和交流的细胞网络的适应还没有被探索。近年来的研究表明，缝隙连接通道在各种组织和病理生理条件下组织对应激和炎症的适应中起着关键作用。缝隙连接促进了相邻细胞之间的直接细胞质通讯，允许参与细胞信号和新陈代谢的小分子分子的转移，并促进组织存活。评估通过缝隙连接在肥胖和糖尿病中与代谢相关的组织(如肝脏和脂肪组织)中的细胞-细胞通讯的潜在作用是这项提议的主要重点。该项目的主要假设是，肥胖诱导的肝脏和脂肪组织中的内质网应激需要增加缝隙连接介导的细胞-细胞通讯，以管理压力，维持组织功能和全身代谢平衡。因此，肝脏和/或脂肪组织缝隙连接的异常激活可能代表了肥胖导致代谢异常的新机制。本研究的目的是评估缝隙连接蛋白(CXS)在肝脏和脂肪组织适应内质网应激、营养过剩和肥胖中的潜在作用。将研究连接蛋白在这些条件下的调节，以及它们改善肥胖症和糖尿病患者组织功能障碍和全身代谢的潜力。彻底了解缝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可能作用，对于全面理解和随后治疗慢性代谢性疾病是重要的。 与公共卫生相关：肥胖症和糖尿病患者胰岛素抵抗的发生机制尚未完全了解。我们的初步结果表明，细胞通过缝隙连接通道的通讯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它们的代谢功能可能是重要的。这项拟议研究的成功完成将阐明肥胖和糖尿病代谢异常发展的新机制。

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.