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.

项目摘要 心力衰竭发生在心肌衰弱，不能充分泵血以满足身体的需要时。 需要血液和氧气。心力衰竭影响着大约600万美国人，并成为一种严重的疾病。 给我们的医疗保健和经济系统带来了巨大的负担。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 一旦适应性的向心性肥大性生长，可能导致纤维化、炎症、心脏功能障碍和 最终心力衰竭尽管这种毁灭性疾病的重要性，我们的理解是不完整的。 心力衰竭进展中的多个事件是未折叠蛋白反应（UPR）的有效诱导剂， 细胞的适应过程，以科普蛋白质折叠的压力。三种信号转导器参与普遍定期审议 以增加蛋白质折叠能力，减少蛋白质折叠的负荷并降解末端错误折叠的蛋白质。 然而，UPR在压力超负荷引起的心肌肥厚和心力衰竭中的作用仍有待进一步研究。 定义了初步研究表明，Xbp 1 s是从酵母到哺乳动物的UPR中最保守的分支， 在心脏中强烈而有力地诱发。心肌细胞中Xbp 1 s的过度表达足以引起 肥厚GFAT 1是己糖胺生物合成途径的限速酶，被发现是 Xbp 1 s的新转录靶点。诱导性GFAT 1过表达导致对 压力过载因此，GFAT 1和己糖胺生物合成可能介导Xbp 1 s诱导的 肥大生长此外，Xbp 1 s过表达导致mTORC 1的强烈激活，这是一种必需的免疫调节因子。 在营养感应和细胞生长中扮演重要角色。因此，Xbp 1可能与UPR、蛋白质折叠、己糖胺 生物合成和细胞生长。本文提出的研究旨在确定Xbp 1/GFAT 1/mTORC 1轴的作用 在压力超负荷引起的心脏肥大和病理性重塑中的作用。获得和失去 将在啮齿动物中采用使用诱导系统的功能方法。心脏综合分析 将进行功能、组织学变化和分子紊乱。体内工作将是 用分离的新生儿心肌细胞进行的体外实验证实了这一点，以进一步破译潜在的 机制等阐明Xbp 1 s/GFAT 1在心肌肥厚和病理性重构中的作用将有助于进一步研究Xbp 1 s/GFAT 1在心肌肥厚和病理性重构中的作用。 大大推进了我们对心力衰竭病理的理解，为未来的临床研究铺平了道路。 应用.