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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

基本信息

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
项目类别：
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

项目摘要

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.