Autonomous and Non-Autonomous Regulation of Cardiac Aging

心脏衰老的自主和非自主调节

• 批准号: 10539319
• 负责人: Hua Bai
• 金额: $ 30.09万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539319
• 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/摘要 衰老与心血管疾病发病率的指数增加有关， 疾病（CVD）。果蝇增龄性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，活性氧产生 （ROS）。细胞质量控制系统，如自噬，是细胞增殖的重要保护机制。 在心脏老化过程中维持组织内稳态。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 并且其对心脏内稳态的作用仍然很大程度上未知。 我们最近的研究揭示了激活素和细胞凋亡机制靶点之间令人兴奋的联系。 雷帕霉素复合物2（mTORC 2）在自噬和心脏衰老的调节中的作用。我们也 注意到两种mTOR复合物（mTORC 1和mTORC 2）似乎在细胞凋亡中起着不同的作用。 自噬调节此外，通过基因筛选，我们确定了几个激活素- 受调节的系统性因素（例如，Upd 3，哺乳动物白细胞介素6，IL-6的果蝇同源物）， 可以介导组织间的通讯并维持心脏的稳态。在本提案中，我们 旨在剖析激活素信号调节自噬和衰老的不同机制， 通过与两个重要途径mTORC 2相互作用的依赖性心脏功能障碍 JAK-STAT为达致整体目标，我们提出两项具体目标。具体目标1： 确定激活素如何与mTORC 2相互作用以调节自噬和心脏衰老;特异性 目的2：确定激活素和更新蛋白3在衰老过程中的作用。 对组织特异性和潜在功能的机制理解， 激活素在心脏衰老中的作用将为它作为一种新的 作为潜在治疗干预目标。

项目成果

Identification of Acetylation Sites of Fatty Acid Synthase (FASN) by Mass Spectrometry and FASN Activity Assay.

• DOI: 10.21769/bioprotoc.4873
• 发表时间: 2023-11-05
• 期刊: BIO-PROTOCOL
• 影响因子: 0.8
• 作者: Miao, Ting;Bai, Hua
• 通讯作者: Bai, Hua

FOXO Regulates Neuromuscular Junction Homeostasis During Drosophila Aging.

• DOI: 10.3389/fnagi.2020.567861
• 发表时间: 2020
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8
• 作者: Birnbaum A;Sodders M;Bouska M;Chang K;Kang P;McNeill E;Bai H
• 通讯作者: Bai H

mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila.

MTORC2通过果蝇的线粒体裂变保护心脏免受高脂饮食诱导的心肌病。

• DOI: 10.3389/fcell.2022.866210
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5

microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle-mediated TGF-β pathway in Drosophila.

microRNA-252 和 FoxO 通过对果蝇中 Dawdle 介导的 TGF-β 途径的双重抑制机制来抑制炎症。

• DOI: 10.1093/genetics/iyab234
• 发表时间: 2022
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Wu,Xiaofen;Niu,Kongyan;Wang,Xiaofan;Zhao,Jing;Wang,Han;Li,Dean;Wang,Hui;Miao,Ting;Yang,Yun;Ma,Huanhuan;Zhang,Yaoyang;Pan,Lei;Liu,Rui;Bai,Hua;Liu,Nan
• 通讯作者: Liu,Nan

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging.

• DOI: 10.3390/antiox11020192
• 发表时间: 2022-01-19
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Kim J;Bai H
• 通讯作者: Bai H