The Role of the Proteasome in Troponin related Cardiomyopathies

蛋白酶体在肌钙蛋白相关心肌病中的作用

基本信息

批准号：
8666792
负责人：
ALDRIN V. GOMES
金额：
$ 37.35万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666792
关键词：
1 year old 26S proteasome Adolescent and Young Adult Affect Calmodulin Cardiac Cardiomyopathies Cardiovascular system Cause of Death Cells Complex Congestive Heart Failure Cyclic AMP-Dependent Protein Kinases Cyclin-Dependent Kinase Inhibitor 3 Developed Countries Diagnosis Enzymes Exhibits Familial Hypertrophic Cardiomyopathy Functional disorder Future Goals Heart Heart Diseases Heart failure Hypertrophy Incidence Inherited Ischemia Lead Left Link Microfilaments Molecular Mouse Cell Line Mus Mutation Patients Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Play Post-Translational Protein Processing Prevalence Proteins Regulation Reperfusion Therapy Role Signal Transduction Site Sudden Death System Tissues Transgenic Mice Troponin Troponin T Ubiquitin Ventricular base insight multicatalytic endopeptidase complex mutant pressure research study

项目摘要

DESCRIPTION (provided by applicant): Despite significant advances in diagnosis and treatment of heart diseases, cardiomyopathies remain the most prevalent cause of death in developed countries. Mutations in cardiac troponin T (cTnT) are responsible for ~7% of all familial hypertrophic cardiomyopathy (FHC) cases. Patients carrying these FHC related cTnT mutations show a high incidence of sudden death without the classical increase in the left ventricular heart wall seen in FHC patients with mutations in other proteins. This proposal focuses on the role of the proteasome in troponin related cardiomyopathies. The molecular mechanisms that regulate the cardiac proteasome and their role in cardiomyopathies are unknown. Transgenic mice expressing a mutant (I79N) cTnT that is associated with FHC exhibited changes in both post-translational modifications of proteasome subunits and the activity of the proteasome, but did not cause significant changes in the expression of the proteasome subunits investigated. Changes in phosphorylation levels of the proteasome were observed concomitant with decreases in all three 20S and 26S proteasome activities. It is critical to understand the importance of the proteasome system in cardiomyopathies to be able to properly target this key proteolytic complex for future cardiovascular benefit. The amount of a key phosphatase associated with the 20S proteasome is also decreased in 20S proteasomes isolated from I79N hearts. This is important since our results also suggest that the kinases and phosphatases associated with the proteasome complex inside the heart are important modulators of the proteasome activity, and that the cardiac proteasome is unlike proteasomes from other tissues. Based upon our results we hypothesize: 1) Significant increases in myofilament Ca2+-sensitivity (>0.1pCa units) contribute to cellular alterations in signaling that lead to proteasome dysfunction which results in increased ubiquitinated proteins and cardiac dysfunction, 2) Some FHC related mutations in troponin directly affect the ability of these proteins to be degraded by the proteasome and alter proteasome activity, and 3) Kinases and phosphatases function as associating proteins for proteasomal complexes in the Troponin-related cardiomyopathies; they play a critical role in modulating the proteasomal function as part of the proteasomal subproteome. To investigate these hypotheses we will investigate three specific aims: 1) To Delineate the Roles of the 20S and 26S Proteasomes in Troponin-related Cardiomyopathies, 2) To Characterize the Temporal Profile of the Proteasome complexes in Troponin-related Cardiomyopathies, and 3) To Characterize Cardiomyopathy Induced Phosphorylation Changes in 26S Proteasomes.

描述（由申请人提供）：尽管心脏病的诊断和治疗取得了重大进展，但心肌病仍然是发达国家最常见的死亡原因。心肌肌钙蛋白 T (cTnT) 突变约占所有家族性肥厚型心肌病 (FHC) 病例的 7%。携带这些 FHC 相关 cTnT 突变的患者猝死发生率很高，而没有出现其他蛋白质突变的 FHC 患者典型的左心室心壁增大的情况。该提案重点关注蛋白酶体在肌钙蛋白相关心肌病中的作用。调节心脏蛋白酶体的分子机制及其在心肌病中的作用尚不清楚。表达与 FHC 相关的突变体 (I79N) cTnT 的转基因小鼠表现出蛋白酶体亚基翻译后修饰和蛋白酶体活性的变化，但并未引起所研究的蛋白酶体亚基表达的显着变化。观察到蛋白酶体磷酸化水平的变化伴随着所有三种 20S 和 26S 蛋白酶体活性的降低。了解蛋白酶体系统在心肌病中的重要性至关重要，以便能够正确靶向这一关键的蛋白水解复合物，从而实现未来的心血管益处。从 I79N 心脏分离的 20S 蛋白酶体中，与 20S 蛋白酶体相关的关键磷酸酶的量也减少。这很重要，因为我们的结果还表明与心脏内蛋白酶体复合物相关的激酶和磷酸酶是蛋白酶体活性的重要调节剂，并且心脏蛋白酶体与其他组织的蛋白酶体不同。根据我们的结果，我们假设：1) 肌丝 Ca2+ 敏感性显着增加（>0.1pCa 单位）导致细胞信号传导改变，导致蛋白酶体功能障碍，从而导致泛素化蛋白增加和心脏功能障碍，2) 一些 FHC 相关突变肌钙蛋白直接影响这些蛋白质被蛋白酶体降解并改变蛋白酶体活性的能力，并且 3) 激酶和磷酸酶的功能如下：肌钙蛋白相关心肌病中蛋白酶体复合物的关联蛋白；它们作为蛋白酶体亚蛋白质组的一部分，在调节蛋白酶体功能方面发挥着关键作用。为了研究这些假设，我们将研究三个具体目标：1) 描述 20S 和 26S 蛋白酶体在肌钙蛋白相关心肌病中的作用，2) 表征肌钙蛋白相关心肌病中蛋白酶体复合物的时间特征，以及 3)表征心肌病诱导的 26S 蛋白酶体磷酸化变化。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice.

DOI：
10.1073/pnas.1716925115
发表时间：
2018-03-06
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Yuan CC;Kazmierczak K;Liang J;Zhou Z;Yadav S;Gomes AV;Irving TC;Szczesna-Cordary D
通讯作者：
Szczesna-Cordary D

Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice.