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

描述（由申请人提供）：肥胖是世界范围内的一个主要问题，它增加了许多疾病的风险，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。内质网应激已被证明在代谢性疾病中发挥重要作用，并与代谢和免疫调节有关。虽然将营养过剩与内质网应激、炎症和胰岛素信号转导中断联系起来的细胞机制已被广泛研究，但在组织水平上作为活细胞和通讯细胞网络的适应尚未被探索。近年来，研究表明，在各种组织和病理生理条件下，间隙连接通道在组织对应激和炎症的适应中起着关键作用。间隙连接促进邻近细胞之间的直接胞质通信，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。在肥胖和糖尿病的代谢相关组织（如肝脏和脂肪组织）中，通过间隙连接评估细胞间通讯的潜在作用是本提案的主要重点。该项目的首要假设是，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，以管理压力，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了肥胖诱导代谢异常的新机制。本研究的目的是评估间隙连接蛋白（connexins [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。这些条件下连接蛋白的调节将被研究，以及它们改善肥胖和糖尿病组织功能障碍和全身代谢的潜力。全面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，对于充分理解和随后治疗慢性代谢性疾病非常重要。

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.