Role of the Xbp1s/GFAT1 axis in pathological cardiac remodelling

项目摘要 心力衰竭发生在心肌功能减弱，不能泵入足够的泵来满足身体的 需要血液和氧气。心力衰竭影响了大约600万美国人，并成为 给我们的医疗和经济体系带来了巨大的负担。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，增加了室壁压力以克服 后负荷压力的增加。心脏随后表现出平行生长以改善壁应力。这 向心性肥大生长，一旦适应，可能会导致纤维化、炎症、心功能障碍和 最终心力衰竭。尽管这种毁灭性的疾病很重要，但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)的有效诱因，a 应对蛋白质折叠压力的细胞适应过程。三个信令换能器参与UPR 增加蛋白质折叠能力，减少蛋白质折叠负荷，降解末端错误折叠的蛋白质。 然而，UPR在压力超负荷诱导的心肌肥厚和心力衰竭中的作用尚不清楚。 已定义。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， 在内心被敏锐而有力地诱导。Xbp1s在心肌细胞中的过度表达足以导致 肥大。GFAT1是氨基己糖生物合成途径的限速酶，被发现是一种 Xbp1s的新转录靶点。GFAT1的可诱导过表达导致对 压力过载。因此，GFAT1和己糖胺的生物合成可能介导Xbp1s诱导的 肥厚性生长。此外，Xbp1s的过度表达导致mTORC1的强烈激活，mTORC1是一种必不可少的 在营养感应和细胞生长方面发挥着重要作用。因此，XBP1可能将UPR、蛋白质折叠、氨基己糖偶联 生物合成和细胞生长。这里提出的研究旨在确定XBP1/GFAT1/mTORC1轴的作用 在心肌肥厚和对压力超负荷的病理重塑中。既有得也有失 使用诱导系统的功能方法将在啮齿类动物中使用。心脏疾病的综合分析 将进行功能、组织学变化和分子错乱。活体工作将是 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 机械装置。Xbp1s/GFAT1在心肌肥厚和病理重塑中的作用 极大地促进了我们对心力衰竭病理的理解，并为未来的临床铺平了道路 申请。

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.