Autonomous and Non-Autonomous Regulation of Cardiac Aging

心脏衰老的自主和非自主调节

• 批准号: 10319560
• 负责人: Hua Bai
• 金额: $ 30.14万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319560
• 关键词: 5' -AMP-activated protein kinase; Activins; Age; Aging; Autophagocytosis; Autophagosome; Calcium; Cardiac; Cardiac Myocytes; Cardiac health; Cardiomyopathies; Cardiovascular Diseases; Cells; Clinical; Communication; Complex; Development; Drosophila genus; Elderly; FRAP1 gene; Genetic Screening; Genetic Transcription; Goals; Heart; Heart Diseases; Hepatocyte; Homeostasis; Hormonal; IL6 gene; Incidence; Interleukin-6; Intervention; Link; Longevity; Maintenance; Mediating; Medical; Mitochondria; Modeling; Molecular; Myocardial dysfunction; Organ; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phosphorylation; Play; Production; Quality Control; Reactive Oxygen Species; Regulation; Research; Role; Signal Pathway; Signal Transduction; Specificity; System; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Vertebrates; age related; biological adaptation to stress; fly; genetic analysis; heart function; novel

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.

项目概要/摘要 衰老与心血管疾病发病率呈指数增加有关 疾病（CVD）。果蝇模型中与年龄相关的心脏变化的几种机制 和脊椎动物已经提出，例如，减少细胞质量控制，改变 钙处理、线粒体损伤增加以及活性氧的产生 （ROS）。细胞质量控制系统，如自噬，是重要的保护机制 心脏衰老过程中组织稳态的维持。众所周知，自噬 随着年龄的增长而下降。然而，年龄依赖性自噬失调的分子基础 其对心脏稳态的贡献仍然很大程度上未知。 我们最近的研究发现了激活素和机械靶点之间令人兴奋的联系 雷帕霉素复合物 2 (mTORC2) 在自噬和心脏衰老调节中的作用。我们也 注意到两个 mTOR 复合物（mTORC1 和 mTORC2）似乎在 自噬调节。此外，通过基因筛选，我们鉴定了几种激活素 调节的全身因子（例如 Upd3、哺乳动物白细胞介素 6、IL-6 的果蝇同源物） 可以介导组织间通讯并维持心脏稳态。在这个提案中，我们 旨在剖析激活素信号调节自噬和年龄的不同机制 通过与两个重要通路 mTORC2 的相互作用来导致依赖性心脏功能障碍 和 JAK-STAT。为实现总体目标，我们提出两个具体目标。具体目标1： 确定激活素如何与 mTORC2 相互作用来调节自噬和心脏衰老；具体的 目标 2：确定衰老过程中激活素和 Upd3 在卵细胞-心脏通讯中的作用。 对组织特异性和潜在功能的机制理解 心脏衰老中的激活素将为其作为一种新型药物的持续发展提供强有力的理由 潜在治疗干预的目标。