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The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation

蛋白酶体和溶酶体降解之间相互作用的 NRF2-p62 轴

基本信息

批准号：
9311709
负责人：
Taixing Cui
金额：
$ 36.24万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
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：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311709
关键词：
Adult Animals Antioxidants Attenuated Binding Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Clinical Management Congestive Heart Failure Diagnosis Disease Excision Feedback Functional disorder GTF2H1 gene Gene Targeting Genetic Genetic Models Goals Healthcare Heart Heart Diseases Heart failure Impairment Injury Knock-out Life Link Literature Measures Mediating Molecular Mus Myocardial Myocardial dysfunction Myocardium Organelles Outcome Pathology Pathway interactions Performance Pharmaceutical Preparations Pharmacology Phase Pilot Projects Play Proteasome Inhibition Proteins Quality Control Research Research Project Grants Role Stress Syndrome System Testing Toxic effect Transgenic Mice Transgenic Organisms Ubiquitin Ubiquitinated Protein Degradation Ubiquitination Up-Regulation cardiogenesis clinical translation constriction human morbidity human mortality hypertensive heart disease in vivo innovation insight misfolded protein multicatalytic endopeptidase complex novel novel therapeutic intervention nuclear factor-erythroid 2 pressure prevent programs protein aggregate protein degradation sham surgery transcription factor virtual

项目摘要

Heart failure is a leading cause of human mortality and morbidity without a cure. Protein degradation by the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) is pivotal to cardiac protein quality control which acts to minimize the level and toxicity of misfolded proteins in cardiomyocytes. Protein quality control inadequacy resulting from UPS and ALP dysfunctions is implicated in the development of heart failure from a variety of heart diseases including pressure overload (PO) disorders. Proteasome inhibition activates ALP while ALP impairment can compromise UPS performance, suggesting an intricate interplay between UPS and ALP dysfunctions. However, such interplay in diseased hearts and its underlying mechanisms remain to be defined. Therefore the long term goal of this research project is to delineate the molecular basis of UPS-ALP crosstalk. Literature and our pilot studies suggest that NRF2 (nuclear factor- erythroid 2-related factor 2) and its target gene p62/SQSTM1 may act as a molecular link in the impairment of UPS performance by ALP insufficiency but this remains to be established in the heart. Hence, we propose to determine the role of the Nrf2-p62 axis in regulating ALP-UPS cross-talk in pressure overloaded hearts. The central hypothesis to be tested is that activation of the Nrf2-p62 axis plays a major mediating role in the impairment of UPS performance by ALP insufficiency in pressure overloaded hearts. We will pursue 2 specific aims. Aim 1 will determine the role of Nrf2 in the induction of cardiac UPS impairment and maladaptive remodeling by ALP impairment in PO hearts. Aim 2 will investigate the molecular mechanism by which Nrf2 exacerbates cardiac injury in ALP insufficient hearts, testing the hypothesis that induction of p62 by Nrf2 impairs UPS performance in ALP deficient hearts. This project will likely provide new mechanistic insight into UPS-ALP interplay in the heart and establish a new concept that enhancing ALP while activating Nrf2 is a better strategy than Nrf2 activation alone for treating heart disease.

心力衰竭是人类死亡和发病的主要原因，但无法治愈。蛋白质降解泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）是心脏蛋白的关键质量控制，其作用是使心肌细胞中错误折叠蛋白质的水平和毒性最小化。蛋白 UPS和ALP功能障碍导致的质量控制不足与心脏的发育有关包括压力超负荷（PO）紊乱在内的各种心脏病导致的衰竭。蛋白酶体抑制激活ALP，而ALP损伤可损害UPS性能，这表明一种复杂的相互作用 UPS和ALP功能障碍之间的联系然而，这种相互作用在患病的心脏和其潜在的机制尚待确定。因此，本研究项目的长期目标是描绘 UPS-ALP串扰的分子基础。文献和我们的初步研究表明，NRF 2（核因子- 红细胞2相关因子2）及其靶基因p62/SQSTM 1可能在红细胞2相关因子2受损中起分子联系作用。 ALP功能不全的UPS性能，但这仍有待建立在心脏。因此，我们建议确定Nrf 2-p62轴在压力超负荷心脏中调节ALP-UPS串扰的作用。的待检验的中心假设是Nrf 2-p62轴的激活在细胞凋亡中起主要的介导作用。压力超负荷心脏中ALP不足对UPS性能的损害我们将继续追求2 具体目标。目的1将确定Nrf 2在诱导心脏UPS损伤和适应不良中的作用。在PO心脏中通过ALP损伤进行重构。目的2将研究Nrf 2在细胞中的作用机制，加剧了ALP不足心脏的心脏损伤，验证了Nrf 2诱导p62的假设，损害ALP缺乏心脏的UPS性能。该项目可能会提供新的机械见解， UPS-ALP在心脏中相互作用，并建立了一个新的概念，即在激活Nrf 2的同时增强ALP是一种新的治疗方法。比单独激活Nrf 2更好的治疗心脏病的策略。