Exploring the molecular mechanisms underlying defective primary cilia in obese-derived mesenchymal stem cells and its significance in obesity

探讨肥胖间充质干细胞初级纤毛缺陷的分子机制及其在肥胖中的意义

• 批准号: 438690235
• 负责人: Professorin Dr. Juping Yuan
• 金额: --
• 依托单位: Klinik für Frauenheilkunde und Geburtshilfe
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/438690235?language=en
• 关键词: Exploring; molecular; mechanisms; underlying; defective

An imbalance of food uptake and energy consumption is one of the predominant health problems worldwide, resulting in obesity with various health consequences including increased risk for type 2 diabetes, cardiovascular diseases and cancer. Obesity perturbs the function of the hypothalamus and peripheral organs like the pancreas, the liver and adipose tissue. Adipose-derived mesenchymal stem/stromal cells (ASCs) are fundamental in the surveillance of adipose tissue homeostasis and become impaired in obesity. The mechanisms underlying this alteration are not well understood. The primary cilium, presented on almost all vertebrate cells, senses and transduces numerous signals. It is crucial in the regulation of ASCs in their various functions such as differentiation. We have recently shown that primary cilia are shortened, non-dynamic and incapable of mediating diverse signals in obese ASCs. Our work suggests a phenomenon whereby obesity related factors including IL6, TNFα and hypoxia impair primary cilia, which render ASCs dysfunctional, fostering inflammation and worsening metabolic dysfunction in obesity. This interesting observation evokes important questions. With this proposal, based on in vivo and in vitro studies using transcriptomic profile analysis, knock-down/knockout gene manipulation, electron microscopy tomography, specific small molecule inhibitors, living cell imaging, as well as other molecular/biochemical methodology with human/mouse primary ASCs and adipose tissues, we would like to address following issues:1. What are the molecular mechanisms responsible for shortening cilia of ASCs in obesity?2. How do shortened cilia lead to dysfunction of ASCs?3. What is the significance of defective ASC cilia in the development of obesity?4. Are shortened primary cilia a general phenomenon for ciliated cells in obesity?We are beginning to appreciate the cardinal importance of primary cilia in health, aging and in diseases like obesity. Defective cilia could be a key event in the pathogenesis of obesity. This study may deliver an alternative and rational strategy to combat obesity by restoring functional cilia in ciliated cells like ASCs.

食物摄取和能量消耗的不平衡是世界范围内的主要健康问题之一，导致肥胖症，具有各种健康后果，包括增加患2型糖尿病、心血管疾病和癌症的风险。肥胖扰乱了下丘脑和周围器官如胰腺、肝脏和脂肪组织的功能。脂肪源性间充质干/基质细胞（ASC）是监督脂肪组织稳态的基础，并在肥胖症中受损。这种改变的机制还不清楚。初级纤毛，存在于几乎所有脊椎动物细胞上，感知和转导许多信号。它在调节ASC的各种功能如分化中至关重要。我们最近的研究表明，在肥胖的ASCs中，初级纤毛缩短，无动力，不能介导多种信号。我们的工作表明，肥胖相关因素，包括IL 6，TNFα和缺氧损害初级纤毛，使ASCs功能障碍，促进炎症和恶化的代谢功能障碍的肥胖的现象。这一有趣的观察引发了一些重要的问题。通过这一提议，基于使用转录组学谱分析、敲低/敲除基因操作、电子显微镜断层扫描、特异性小分子抑制剂、活细胞成像以及人/小鼠原代ASC和脂肪组织的其他分子/生物化学方法的体内和体外研究，我们希望解决以下问题：1. 肥胖症中ASCs纤毛缩短的分子机制是什么？2. 纤毛缩短如何导致ASCs功能障碍？3. 有缺陷的ASC纤毛在肥胖症的发展中有什么意义？4. 初级纤毛缩短是肥胖患者纤毛细胞的普遍现象吗？我们开始意识到初级纤毛在健康、衰老和肥胖等疾病中的重要性。纤毛缺陷可能是肥胖症发病机制中的一个关键事件。这项研究可能提供一种替代和合理的策略，通过恢复纤毛细胞如ASCs中的功能纤毛来对抗肥胖。