Autonomous and Non-Autonomous Regulation of Cardiac Aging

项目摘要/摘要 老龄化与心血管疾病发病率呈指数级增长有关 疾病(CVD)。苍蝇模型增龄相关心脏变化的几种机制 而脊椎动物已经被提出，例如，降低细胞质量控制，改变 钙处理，增加线粒体损伤，以及产生活性氧物种 (ROS)。细胞质量控制系统，如自噬，是重要的保护机制 心脏老化过程中组织内稳态的维持。众所周知，自噬 随着年龄的增长而下降。然而，与年龄相关的自噬失调的分子基础 它对心脏稳态的贡献在很大程度上仍不清楚。 我们最近的研究揭示了激活素和机制靶点之间令人兴奋的联系 雷帕霉素复合体2(MTORC2)在自噬和心脏老化中的调节作用我们也 注意到两个mTOR复合体(mTORC1和mTORC2)似乎在 自噬调节。此外，通过基因筛查，我们发现了几种激活素- 受调节的系统因子(例如，UPD3，哺乳动物白细胞介素6，IL-6的苍蝇同源物)， 能调节组织间的沟通，维持心脏内环境的稳定。在这项提案中，我们 目的剖析激活素信号调节自噬和年龄的不同机制。 通过与两个重要途径mTORC2的相互作用而导致的依赖性心功能障碍 和JAK-STAT。为了实现这一总体目标，我们提出了两个具体目标。具体目标1： 确定激活素如何与mTORC2相互作用调节自噬和心脏老化；特异性 目的2：探讨激活素和UPD3在衰老过程中卵母细胞-心脏通讯中的作用。 对组织特异性和潜在功能的机械性理解 心脏老化中的激活素将为其作为一种新型药物的继续发展提供强有力的理由 潜在治疗干预的目标。

Project Summary/Abstract Aging is associated with an exponential increase in the incidence of cardiovascular diseases (CVD). Several mechanisms underlying age-associated cardiac changes in fly model and vertebrates have been proposed, for example, decreased cellular quality control, altered calcium handling, increased mitochondria damage, and the production of reactive oxygen species (ROS). Cellular quality control systems, like autophagy, are essential protective mechanisms for the maintenance of tissue homeostasis during cardiac aging. It is well-known that autophagy declines with age. However, the molecular basis for age-dependent dysregulation of autophagy and its contribution to cardiac homeostasis remain largely unknown. Our recent studies uncovered an exciting link between activin and mechanistic target of rapamycin complex 2 (mTORC2) in the regulation of autophagy and cardiac aging. We also noticed that two mTOR complexes (mTORC1 and mTORC2) seem to play distinct roles in autophagy regulation. Furthermore, through genetic screening we identified several activin- regulated systemic factors (e.g., Upd3, the fly homology of mammalian Interleukin 6, IL-6) that can mediate tissue-tissue communication and maintain cardiac homeostasis. In this proposal, we aim to dissect the distinct mechanisms by which activin signaling regulate autophagy and age- dependent cardiac dysfunctions through the interactions with two important pathways, mTORC2 and JAK-STAT. To achieve the overall objective, we propose two specific aims. Specific Aim 1: Determine how activin interacts with mTORC2 to regulate autophagy and cardiac aging; Specific Aim 2: Determine the role of activin and Upd3 in oenocyte-heart communication during aging. The mechanistic understanding of the tissue specificity and the underlying function of activin in cardiac aging will provide strong justification for its continued development as a novel target for potential therapeutic intervention.