Role of the Xbp1s/GFAT1 axis in pathological cardiac remodelling

Xbp1s/GFAT1 轴在病理性心脏重塑中的作用

• 批准号: 10584092
• 负责人: Zhao Wang
• 金额: $ 30.18万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584092
• 关键词: Role; Xbp1s; GFAT1; axis; pathological

Project Summary Heart failure occurs when the cardiac muscle is weakened and cannot pump sufficiently to meet the body's need for blood and oxygen. Heart failure affects approximately 6 million of Americans and becomes a tremendous burden on our healthcare and economy system. Hypertension is one of the most prominent risk factors of heart failure. In response to high blood pressure, ventricular wall stress is augmented to overcome the increase of afterload pressure. The heart then manifests parallel growth to ameliorate wall stress. This concentric hypertrophic growth, once adaptive, may lead to fibrosis, inflammation, cardiac dysfunction and eventually heart failure. Despite the important of this devastating disease, our understanding is incomplete. Multiple events in heart failure progression are potent inducers of the unfolded protein response (UPR), a cellular adaptive process to cope with protein-folding stress. Three signaling transducers participate in the UPR to increase protein-folding capacity, reduce load of protein-folding and degrade terminally misfolded proteins. However, the role of the UPR in pressure overload-induced cardiac hypertrophy and heart failure remains to be defined. Preliminary work shows that Xbp1s, the most conserved branch of the UPR from yeast to mammals, is acutely and potently induced in heart. Overexpression of Xbp1s in cardiomyocyte is sufficient to cause hypertrophy. GFAT1, the rate-limiting enzyme of the hexosamine biosynthetic pathway, is discovered as a novel transcriptional target of Xbp1s. Inducible overexpression of GFAT1 leads to more profound response to pressure overload. GFAT1, and the hexosamine biosynthesis, may therefore mediate Xbp1s-induced hypertrophic growth. Moreover, Xbp1s overexpression leads to strong activation of mTORC1, an essential player in nutrient sensing and cell growth. Xbp1s may therefore couple the UPR, protein-folding, hexosamine biosynthesis and cell growth. Studies proposed here aim to define the role of the Xbp1/GFAT1/mTORC1 axis in cardiac hypertrophy and pathological remodelling in response to pressure overload. Both gain- and loss-of- function approaches using inducible systems will be employed in rodents. Comprehensive analysis for cardiac function, histological changes, and molecular derangements will be conducted. In vivo work will be corroborated by in vitro experiments with isolated neonatal myocytes to further decipher underlying mechanisms. Elucidation of the role of Xbp1s/GFAT1 in cardiac hypertrophy and pathological remodelling will greatly advance our understanding of the pathology of heart failure and pave a way for future clinical applications.

项目概要 当心肌衰弱并且不能充分泵血以满足身体的需要时，就会发生心力衰竭。 需要血液和氧气。心力衰竭影响大约 600 万美国人，并成为 对我们的医疗保健和经济系统造成巨大负担。高血压是最突出的风险之一 心力衰竭的因素。为了应对高血压，心室壁应力增加以克服 后负荷压力的增加。然后心脏表现出平行生长以改善壁应力。这 同心肥大性生长一旦适应，可能会导致纤维化、炎症、心脏功能障碍和 最终导致心力衰竭。尽管这种毁灭性疾病很重要，但我们的理解并不完整。 心力衰竭进展中的多个事件是未折叠蛋白反应（UPR）的有效诱导物，UPR是一种 细胞应对蛋白质折叠应激的适应性过程。三个信号传感器参与 UPR 增加蛋白质折叠能力，减少蛋白质折叠负荷并降解末端错误折叠蛋白质。 然而，UPR 在压力超负荷引起的心脏肥大和心力衰竭中的作用仍有待研究。 定义的。初步研究表明，Xbp1s是从酵母到哺乳动物的UPR中最保守的分支， 在心脏中强烈而强烈地诱发。 Xbp1s 在心肌细胞中的过度表达足以导致 肥大。 GFAT1 是己糖胺生物合成途径的限速酶，被发现是一种 Xbp1s 的新转录靶标。 GFAT1 的诱导性过度表达会导致更深刻的反应 压力过载。因此，GFAT1 和己糖胺生物合成可能介导 Xbp1s 诱导的 肥大性生长。此外，Xbp1s 过度表达会导致 mTORC1 的强烈激活，mTORC1 是一种重要的 营养传感和细胞生长领域的参与者。因此，Xbp1s 可能偶联 UPR、蛋白质折叠、己糖胺 生物合成和细胞生长。这里提出的研究旨在定义 Xbp1/GFAT1/mTORC1 轴的作用 心脏肥大和响应压力超负荷的病理重塑。既有得失也有失 使用诱导系统的功能方法将应用于啮齿动物。心脏综合分析 将进行功能、组织学变化和分子紊乱。体内工作将 通过分离的新生儿肌细胞的体外实验证实，以进一步破译潜在的 机制。阐明 Xbp1s/GFAT1 在心脏肥大和病理重塑中的作用将 极大地增进了我们对心力衰竭病理学的理解，为未来的临床铺平了道路 应用程序。