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.

项目总结/文摘