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; 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.

抽象的 TGF-β几乎影响从早期胚胎发育到成人的哺乳动物生理的所有方面 通过调节各种细胞功能，包括增殖，分化和 凋亡。尽管存在增量，但TGF-β信号传导在细胞代谢中也起着重要作用 了解它如何不同地调节线粒体生物发生，呼吸和细胞器的进展 破坏。理论上将这种变化的影响主要通过缓慢作用的上下文基因发生 调节，TGF-β还能够诱导线粒体形状更快，直接和可逆的变化 通过在很大程度上未知机制的功能 - 代表重要知识差距的关键方面 在现场。我们的研究计划重点是两种强大的反对机制 TGF-β效应器SMAD2和TAK1，控制线粒体融合/裂变动力学以实现和维持 代谢稳态。我们寻求了解管理其组织，激活和的机制 线粒体重塑的调节以及它们如何使用血管生成作为A 发展模型系统。我们的研究将提供有关复杂TGF-β信号如何传导的独特观点 网络控制线粒体动力学，以影响其代谢，发育和稳态角色 血管生理。