ER Stress and Protein Dynamics in Cardiac Remodeling

心脏重塑中的内质网应激和蛋白质动力学

• 批准号: 9205257
• 负责人: Maggie Lam
• 金额: $ 12.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205257
• 关键词: ATF6 gene; Alpha Cell; Amination; Amines; Biological Assay; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cell Surface Receptors; Cells; Clinical; Data; Development; Disease; Endoplasmic Reticulum; Environment; Faculty; Functional disorder; Funding; Genetic; Glycoproteins; Goals; Health; Heart; Heart Diseases; Heart failure; Heat shock proteins; Homeostasis; Human; Hypertrophy; Impairment; In Vitro; Isoproterenol; Knowledge; Label; Measures; Membrane; Membrane Glycoproteins; Membrane Proteins; Metabolic; Methods; Mind; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Myocardium; NRP1 gene; Names; Neuropilin-1; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Phase; Physiological; Process; Professional Competence; Protein Biosynthesis; Protein Dynamics; Protein Glycosylation; Proteins; Proteome; Proteomics; Research; Resolution; Rodent; Role; Sampling; Sarcolemma; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Site; Structure; Techniques; Technology; Testing; Training; XBP1 gene; base; biological adaptation to stress; clinically relevant; effective therapy; endoplasmic reticulum stress; experimental study; glycoproteomics; glycosylation; in vivo; in vivo Model; insight; mortality; mouse model; new technology; new therapeutic target; novel; protein degradation; protein expression; protein function; proteostasis; receptor; response; translational study; virtual

 DESCRIPTION (provided by applicant): Heart failure is a leading cause of morbidity and mortality worldwide. The search for effective treatments hinges upon understanding the molecular underpinnings of the adverse hypertrophy and remodeling that precipitates cardiac failure. Recent research implicates endoplasmic reticulum (ER) stress as a virtually universal feature of heart diseases, but detailed mechanisms of how ER stress contributes to maladaptive cardiac remodeling are currently lacking. My colleagues and I recently developed a novel technological platform and used it to discover that cardiac remodeling amid ER stress is associated with widespread disruption in protein turnover dynamics, including importantly a cluster of ER-associated glycoproteins with aberrant proteostasis. Within the cluster, cardiac remodeling in particular severely disrupts the dynamics and glycosylation of neuropilin-1 (NRP1), a cell surface glycoprotein that is thought to be salubrious to the failing heart. These observations endorse my postulate that ER stress contributes to maladaptive remodeling via effecting aberrant cardiac protein homeostasis and glycosylation. Hence, the goal of the current proposal is to define the molecular consequences of ER stress in the myocardium by investigating three proteostasis parameters - protein expression, turnover dynamic and glycosylation - amid ER stress and cardiac remodeling. The short-term (K99) aims are to (1) understand how ER stress impacts the expression and dynamics of ER-associated proteins in mouse models, and (2) characterize the impact of protein dynamics and glycosylation on cardiac NRP1 protein interactions in health and in disease. These studies are a logical extension of my current research, and will give me opportunities to train in rodent and cell culture models of ER stress and cardiac remodeling, as well as translational studies of clinical human heart failure samples. With this development in mind, my long-term (R00) aims are to (3) investigate how protein glycosylation remodels in the cardiac proteome at large, using a combination of in vitro and in vivo models I will have trained in during my K99 phase, and (4) investigate how protein glycosylation impacts the physiological role of NRP1 signaling in the failing heart. The propose studies will be the first to systemically examine how ER stress impacts the essential ER functions of protein turnover and glycosylation as a pathogenic mechanism, and will thereby lend insights to our understanding of adverse remodeling. Altogether, the training plan and supportive institutional environment at UCLA will equip me with the experimental and career skills to ask a wide range of questions regarding ER stress and hypertrophy as an independent tenured faculty.

 描述（由适用提供）：心力衰竭是全球发病率和死亡率的主要原因。寻求有效治疗的方法在了解不良肥大的分子基础并重塑了珍贵心脏衰竭时取决于铰链。最近的研究将内质网（ER）压力视为心脏病的普遍特征，但是目前缺乏有关ER应力如何导致不良心脏心脏重塑的详细机制。我和我的同事们最近开发了一个新颖的技术平台，并用它来发现ER应力与蛋白质周转动力学的宽度破坏有关，包括重要的是一群具有异常蛋白质抑制剂的ER相关糖蛋白。在簇中，心脏重塑尤其严重破坏了神经蛋白-1（NRP1）的动力学和糖基化，这是一种细胞表面糖蛋白，被认为对失败的心脏有利。这些观察结果认可我的假设，即ER应力通过影响异常心脏蛋白稳态和糖基化而导致不良适应性重塑。因此，当前建议的目的是通过研究三种蛋白质抑制参数来定义心肌中质心质网应激的分子后果 - 蛋白质表达，转离动态和糖基化 - 在ER应力和心脏重塑中。短期（K99）的目的是（1）了解ER应力如何影响小鼠模型中ER相关蛋白的表达和动力学，（2）（2）表征蛋白质动力学和糖基化对心脏NRP1蛋白相互作用在健康和疾病中的影响。这些研究是我当前研究的逻辑扩展，将使我有机会训练ER应力和心脏重塑的啮齿动物和细胞培养模型，以及对临床人类心力衰竭样品的翻译研究。考虑到这一发展，我的长期（R00）的目的是（3）研究蛋白质糖基化重塑整个心脏蛋白质组中的蛋白质糖基化重塑如何使用体外和体内模型的组合，我将在K99阶段进行培训，（4）（4）蛋白质糖基化如何研究NRP1信号的身体作用如何影响NRP1信号的身体作用。该提案研究将是第一个系统地研究ER应力如何影响蛋白质更新和糖基化作为致病机制的基本ER功能，从而为我们理解不良重塑的理解提供了见解。总而言之，加州大学洛杉矶分校的培训计划和支持机构环境将使我具备实验和职业技能，以提出有关ER压力和肥大作为独立终身教师的广泛问题。