The ER Stress-Induced Selenoprotein, SelenoS, Regulates Proteostasis and Cardiac Hypertrophy

内质网应激诱导的硒蛋白 SelenoS 可调节蛋白质稳态和心脏肥大

基本信息

批准号：
10550149
负责人：
Chris Glembotski
金额：
$ 42.67万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10550149
关键词：
ATF6 gene Address Affect Antioxidants Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Line Cell Size Cell model Cells Cessation of life Complex Diet Ectopic Expression Elements Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Ensure Equilibrium Exercise Gene Expression Goals Growth Heart Heart Contractilities Heart Diseases Heart Hypertrophy Heart failure Hypertrophy IGF1 gene Impairment Investigation Knowledge Lead Life Mediating Membrane Modeling Molecular Molecular Genetics Mus Muscle Cells Mutate Neonatal Nodal Organ Pathologic Phenylephrine Physiological Play Process Protein Biosynthesis Protein Secretion Proteins Proteome Rattus Regulation Role Selenium Site Stimulus Structure Transcript Ventricular Work cardiovascular health endoplasmic reticulum stress genetic approach heart function heart preservation in vivo innovation knock-down misfolded protein mortality mouse model mutant overexpression pressure protein degradation protein expression protein folding proteostasis receptor recruit rodent genome selenoprotein sensor transcription factor

项目摘要

Project Summary Many forms of cardiovascular disease lead to pathological cardiac hypertrophy, which is maladaptive because it causes reduced contractility of the heart, resulting in life-threatening heart failure. In contrast, exercise can cause the heart to grow in a functionally adaptive way; this is defined as physiological cardiac hypertrophy. Our long-term goal is to achieve a better mechanistic understanding of both forms of heart growth. In this proposal, we will address this understanding by examining roles for selenium (Se) in cardiac hypertrophy. Se, which is an essential element in our diet, is well known to be required for cardiovascular health, though the precise role played by Se the cardiovascular system is not known. A major role for Se in all organs and cells is that it is a key component of selenoproteins; here, we will examine the function of Se in selenoproteins in the heart. Our specific objective is to examine the selenoprotein, SelenoS, which we believe to be required for both pathological and physiological cardiac hypertrophy. We will conduct this investigation in mouse models of cardiac hypertrophy using molecular genetic approaches to selectively and specifically impair or enhance the function of SelenoS, followed by studies to determine the effects of these maneuvers on heart structure and function. One mechanistic point we will be addressing is how Se affects heart growth. However, since there are 23 other proteins in mice that require Se, in order to focus our approach on determining how Se is used by only SelenoS in the heart, we will examine the effects of a mutant form of SelenoS, SelenoS-Se, which is different from SelenoS only in that it does not have Se. In this way, we will be able to mechanistically pinpoint how Se on just SelenoS works to support cardiac growth, because all of the other selenoproteins will still have Se incorporated into their structures. SelenoS is also involved in the adaptive degradation of misfolded proteins in the endoplasmic reticulum, a process called ERAD. We will also examine the effects of SelenoS, SelenoS-Se, and a form of SelenoS that cannot function in ERAD, Seleno-ERAD, on cardiac growth. Our specific aims are to 1- determine the effects of depleting endogenous SelenoS on cardiac structure, function, gene and protein expression in mouse models of cardiac hypertrophy, 2- examine the effects of ectopic expression of SelenoS, Seleno-ERAD and SelenoS-Se in mice in which endogenous SelenoS has been knocked down on pathological and physiological cardiac hypertrophy, and 3- assess how SelenoS, Seleno-ERAD and SelenoS-Se affect the structure and function of the ERAD complex.

项目摘要多种形式的心血管疾病导致病理心脏肥大，这是适应不良的，因为它导致心脏收缩性降低，导致威胁生命的心力衰竭。相反，运动可以使心脏以功能自适应的方式生长；这被定义为生理心脏肥大。我们的长期目标是对两种形式的心脏增长有更好的机械理解。在此提案中，我们将通过检查心脏肥大中硒（SE）的作用来解决这种理解。 SE，那是我们饮食中的一个重要元素是心血管健康所必需的，尽管是确切的角色由SE播放的心血管系统尚不清楚。 SE在所有器官和细胞中的主要作用是硒蛋白的关键成分；在这里，我们将检查SE在心脏中硒蛋白中的功能。我们的具体目标是检查硒蛋白，硒蛋白，我们认为这是两者都需要的病理和生理心脏肥大。我们将在鼠标模型中进行此调查使用分子遗传学方法的心脏肥大，有选择地有理由损害或增强硒的功能，然后进行研究，以确定这些操纵对心脏结构和功能。我们将要解决的一个机械点是SE如何影响心脏的生长。但是，由于有 23小鼠中需要SE的其他蛋白质，以将我们的方法集中在确定SE仅使用的方法上硒中的硒，我们将检查硒的突变形式的硒，这是不同的仅来自硒，只有它没有SE。这样，我们将能够机械地查明如何SE 在Just Selenos上致力于支持心脏增长，因为所有其他硒蛋白仍然将具有SE 纳入其结构。 Selenos还参与了错误折叠蛋白的自适应降解内质网，称为Erad的过程。我们还将研究硒，硒，SEL，以及一种无法在心脏增长的Erad，Seleno-Erad中起作用的硒。我们的具体目标是 1-确定耗尽内源性硒对心脏结构，功能，基因和蛋白质的影响在心脏肥大的小鼠模型中，2-检查硒异位表达的影响，硒埃拉德（Seleno-Erad）和硒sse的小鼠中，内源性硒被击倒了病理学和生理心脏肥大，3-评估硒，硒，埃伦诺斯和硒如何影响 ERAD复合物的结构和功能。