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

基本信息

批准号：
10170415
负责人：
Zhao Wang
金额：
$ 10.32万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-12-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170415
关键词：
ATF6 gene Acute Affect American Anabolism Blood Calcium Signaling Cardiac Cardiac Myocytes Cell physiology Complex Couples Coupling Data Dependence Disease Enzymes Epidemic Event FRAP1 gene Fibrosis Future Genetic Transcription Glucose Growth Growth Factor Healthcare Healthcare Systems Heart Heart Diseases Heart Hypertrophy Heart failure Hexosamines Histologic Homeostasis Hypertension Hypertrophy In Vitro Inflammation Ischemia Lead Light Link Mammals Mediating Metabolic Molecular Muscle Cells Myocardial Ischemia Myocardial dysfunction Myocardium Neonatal Oxygen Pathologic Pathology Pathway interactions Process Protein Biosynthesis Proteins Pump Reperfusion Injury Reperfusion Therapy Risk Factors Rodent Role Signal Pathway Signal Transduction Stress System TSC2 gene Testing Transducers Ventricular Work XBP1 gene Yeasts arm base cardioprotection cell growth clinical application conditional knockout detection of nutrient experimental study heart function in vivo inducible gene expression insight loss of function misfolded protein mouse model novel novel therapeutic intervention overexpression pressure protein folding response transcription factor

项目摘要

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.

项目摘要心力衰竭会在心脏肌肉被削弱并且无法充分泵送以达到身体时会发生心力衰竭需要血液和氧气。心力衰竭会影响约600万美国人，并成为我们的医疗保健和经济体系负担很大。高血压是最突出的风险之一心力衰竭的因素。为了响应高血压，心室壁应力增加以克服后负荷压力的增加。然后，心脏表现出平行的生长与缓解壁应力。这一旦自适应，同心肥厚的生长可能会导致纤维化，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）的有效诱导者细胞自适应过程以应对蛋白质折叠应激。三个信号传感器参与UPR 为了增加蛋白质折叠能力，请减少蛋白质折叠的负荷并降解终末错误折叠的蛋白质。但是，UPR在压力超负荷引起的心脏肥大和心力衰竭中的作用仍然是定义。初步工作表明，XBP1是从酵母到哺乳动物的UPR最保守的分支，敏锐而有效地诱导心脏。心肌细胞中XBP1的过表达足以引起肥大。 GFAT1是己糖胺生物合成途径的速率限制酶，被发现为 XBP1S的新型转录靶标。 GFAT1的诱导过表达导致对压力超负荷。 GFAT1和己糖胺生物合成，因此可以介导XBP1S诱导肥厚的生长。此外，XBP1的过表达导致MTORC1强烈激活，这是必不可少的营养感应和细胞生长的参与者。因此，XBP1可以将UPR（蛋白质折叠，己胺）搭配生物合成和细胞生长。这里提出的研究旨在定义XBP1/GFAT1/MTORC1轴的作用在心脏肥大和病理重塑中，响应压力超负荷。收益和丧失啮齿动物将采用使用诱导系统的功能方法。心脏的全面分析功能，组织学变化和分子扰动将进行。体内工作将是通过用孤立的新生儿肌细胞进行体外实验来证实机制。阐明XBP1/GFAT1在心脏肥大和病理重塑中的作用将大大提高了我们对心力衰竭病理的理解，并为未来的临床铺平了一种方式申请。