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: 9034347
• 负责人: Maggie Lam
• 金额: $ 11.82万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034347
• 关键词: 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; In Vitro; Isoproterenol; Knowledge; Label; Measures; Membrane; Membrane Glycoproteins; Membrane Proteins; Metabolic; Methods; Mind; Mining; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Myocardium; Names; Neuropilin-1; Pathogenesis; Pathway interactions; Phase; Physiological; Process; Professional Competence; Protein Biosynthesis; Protein Dynamics; Protein Glycosylation; Proteins; Proteome; Proteomics; Receptor Signaling; Research; Resolution; Rodent; Role; Sampling; Sarcolemma; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Site; Staging; Structure; Techniques; Technology; Testing; Training; base; biological adaptation to stress; clinically relevant; effective therapy; endoplasmic reticulum stress; glycoproteomics; glycosylation; in vivo; in vivo Model; insight; mortality; mouse model; new technology; new therapeutic target; novel; protein degradation; protein expression; protein function; receptor; research study; response; stress protein; translational study

 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(由申请人提供)：心力衰竭是全球发病率和死亡率的主要原因。寻找有效的治疗方法取决于了解导致心力衰竭的不利肥厚和重塑的分子基础。最近的研究表明，内质网(ER)应激几乎是心脏疾病的普遍特征，但内质网应激如何导致适应性不良的心脏重构目前缺乏详细的机制。我和我的同事最近开发了一个新的技术平台，并利用它发现内质网应激下的心脏重塑与蛋白质周转动力学的广泛干扰有关，重要的是，包括一簇具有异常蛋白平衡的内质网相关糖蛋白。在该簇中，心脏重构尤其严重扰乱了神经毛细蛋白-1(Nrp1)的动力学和糖基化，Nrp1是一种细胞表面糖蛋白，被认为对衰竭的心脏有益。这些观察结果支持了我的假设，即内质网应激通过影响异常的心脏蛋白稳态和糖基化来促进适应性不良的重塑。因此，本研究的目的是通过研究内质网应激和心脏重构中的三个蛋白平衡参数--蛋白质表达、周转动力学和糖基化--来确定内质网应激在心肌中的分子后果。短期(K99)的目的是(1)了解内质网应激如何影响小鼠模型中内质网相关蛋白的表达和动态，以及(2)表征蛋白质动力学和糖基化对健康和疾病中心脏Nrp1蛋白相互作用的影响。这些研究是我目前研究的合理扩展，将使我有机会培训内质网应激和心脏重塑的啮齿动物和细胞培养模型，以及临床人类心力衰竭样本的翻译研究。考虑到这一发展，我的长期目标(R00)是(3)使用我将在K99阶段训练的体外和体内模型的组合，研究蛋白质糖基化如何在整个心脏蛋白质组中重塑，以及(4)研究蛋白质糖基化如何影响Nrp1信号在衰竭心脏中的生理作用。这项研究将首次系统地研究内质网应激如何影响作为致病机制的蛋白质周转和糖基化的基本内质网功能，从而有助于我们对不利重构的理解。总之，加州大学洛杉矶分校的培训计划和支持性的机构环境将使我具备实验和职业技能，作为一名独立的终身教职员工，我可以提出一系列关于ER压力和肥大的问题。