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.

心力衰竭是无法治愈的人类死亡率和发病率的主要原因。蛋白质降解泛素 - 蛋白酶体系统（UPS）和自噬 - 溶糖途径（ALP）对心脏蛋白是关键的质量控制可以最大程度地减少心肌细胞中错误折叠蛋白的水平和毒性。蛋白质 UPS和ALP功能障碍引起的质量控制不足与心脏的发展有关包括压力超负荷（PO）疾病在内的各种心脏病的失败。蛋白酶体抑制激活ALP，而ALP损伤会损害UPS的性能，这表明了复杂的相互作用在UPS和ALP功能障碍之间。但是，这种相互作用在患病的心脏及其基础上机制仍有待定义。因此，该研究项目的长期目标是描述 UPS-ALP串扰的分子基础。文献和我们的试点研究表明NRF2（核因子 - 红细胞2相关因子2）及其靶基因P62/SQSTM1可能充当损害的分子联系 ALP功能不全的表现，但这在心脏中仍有待确定。因此，我们建议确定NRF2-P62轴在压力超载心脏中调节ALP-UP串扰的作用。这要测试的中央假设是NRF2-P62轴的激活在 ALP不足在压力超负荷心脏中损害UPS性能。我们将追求2 具体目标。 AIM 1将确定NRF2在诱导心脏UPS损伤和适应不良的诱导中的作用在PO Hearts中通过ALP损害进行重塑。 AIM 2将研究NRF2的分子机制加剧心脏心脏不足的心脏损伤，检验了NRF2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洞察力在心脏中的UPS ALP相互作用，并建立一个新概念，在激活NRF2时增强ALP是一个与单独治疗心脏病的NRF2激活相比，策略更好。