TGF-beta signaling in mitochondrial dynamics

线粒体动力学中的 TGF-β 信号传导

• 批准号: 10550422
• 负责人: Nam Y Lee
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550422
• 关键词: Adult; Affect; Apoptosis; Biogenesis; Biological Models; Blood Vessels; Cell physiology; Cellular Metabolic Process; Complex; Defect; Development; Embryonic Development; Gene Expression Regulation; Homeostasis; Knowledge; MAP3K7 gene; Metabolic; Metabolic Diseases; Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Oxidative Stress; Physiology; Play; Production; Proliferating; Regulation; Research; Respiration; Role; Shapes; Signal Transduction; Tissues; Transforming Growth Factor beta; angiogenesis; cell behavior; novel; programs; theories; virtual

ABSTRACT TGF-β affects virtually all aspects of mammalian physiology starting from early embryonic development to adult tissue homeostasis through regulation of diverse cellular functions including proliferation, differentiation, and apoptosis. TGF-β signaling also plays an important role in cell metabolism, although there has been incremental progress in understanding how it differentially regulates mitochondrial biogenesis, respiration, and organelle destruction. While such varying effects are theorized to occur primarily through slow-acting contextual gene regulation, TGF-β is also capable of inducing more rapid, direct, and reversible changes in mitochondrial shape and function through largely unknown mechanisms− a key aspect that represents an important knowledge gap in the field. Our research program has focused on two powerfully opposing mechanisms by which two major TGF-β effectors, Smad2 and TAK1, control mitochondrial fusion/fission dynamics to achieve and maintain metabolic homeostasis. We seek to understand mechanisms governing their organization, activation, and regulation in mitochondrial remodeling and how they influence cell behavior using angiogenesis as a developmental model system. Our studies will provide unique perspectives on how the complex TGF-β signaling networks control mitochondrial dynamics to affect their metabolic, developmental and homeostatic roles in vascular physiology.

摘要 TGF-β几乎影响从早期胚胎发育到成年的哺乳动物生理学的所有方面 通过调节多种细胞功能（包括增殖、分化和 凋亡TGF-β信号传导在细胞代谢中也起着重要作用，尽管已经有越来越多的 了解它如何差异调节线粒体生物发生，呼吸和细胞器的进展 杀伤性虽然这种不同的影响理论上主要是通过缓慢作用的背景基因发生的， 在调节过程中，TGF-β还能够诱导线粒体形状发生更快速、直接和可逆的变化 并通过很大程度上未知的机制发挥作用-这是一个代表重要知识差距的关键方面 在外地我们的研究计划集中在两个强大的对立机制，其中两个主要的 TGF-β效应子Smad 2和TAK 1控制线粒体融合/分裂动力学，以实现和维持 代谢平衡我们试图了解管理其组织，激活， 调节线粒体重塑以及它们如何影响细胞行为，使用血管生成作为 发展模式体系我们的研究将为复杂的TGF-β信号传导如何 网络控制线粒体动力学，以影响其代谢，发育和稳态作用， 血管生理学