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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：
10218914
负责人：
Chris Glembotski
金额：
$ 38.4万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218914
关键词：
ATF6 gene Address Affect Antioxidants Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system 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 Modeling Molecular Molecular Genetics Mus Muscle Cells Mutate Neonatal Nodal Organ Pathologic Phenylephrine Physiological Play Process Protein Biosynthesis Proteins Proteome Rattus Regulation Rodent Role Selenium Site Stimulus Structure Time Transcript Ventricular Work base 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 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.

项目概要许多形式的心血管疾病都会导致病理性心脏肥大，这是适应不良的，因为它会导致心脏收缩力下降，导致危及生命的心力衰竭。相比之下，运动可以使心脏以功能适应的方式生长；这被定义为生理性心脏肥大。我们的长期目标是更好地理解这两种形式的心脏生长的机制。在这个提案中，我们将通过研究硒 (Se) 在心脏肥大中的作用来加深对这一理解。 Se，即众所周知，它是我们饮食中的重要元素，是心血管健康所必需的，但其确切作用 Se 对心血管系统的作用尚不清楚。硒在所有器官和细胞中的一个主要作用是，它是硒蛋白的关键成分；在这里，我们将检查硒在心脏中的硒蛋白中的功能。我们的具体目标是检查硒蛋白 SelenoS，我们认为这对于两者都是必需的病理性和生理性心脏肥大。我们将在小鼠模型中进行这项研究使用分子遗传学方法选择性地、特异性地损害或增强心脏肥大 SelenoS 的功能，随后进行研究以确定这些操作对心脏结构和功能。我们要解决的一个机制问题是硒如何影响心脏生长。然而，由于有小鼠体内 23 种其他蛋白质需要 Se，以便将我们的方法集中于确定仅 SelenoS 在心脏中，我们将检查 SelenoS 的突变形式 SelenoS-Se 的作用，它是不同的与 SelenoS 的区别仅在于它不含 Se。通过这种方式，我们将能够机械地查明Se是如何仅 SelenoS 可以支持心脏生长，因为所有其他含硒蛋白仍含有 Se 纳入他们的结构。 SelenoS 还参与错误折叠蛋白的适应性降解内质网，这个过程称为 ERAD。我们还将检查 SelenoS、SelenoS-Se、 SelenoS 的一种形式，不能在 ERAD 中发挥作用，Seleno-ERAD，对心脏生长有影响。我们的具体目标是 1-确定消耗内源性 SelenoS 对心脏结构、功能、基因和蛋白质的影响心脏肥大小鼠模型中的表达，2-检查 SelenoS 异位表达的影响，小鼠中的 Seleno-ERAD 和 SelenoS-Se，其中内源性 SelenoS 已在病理学上被敲低和生理性心脏肥大，以及 3- 评估 SelenoS、Seleno-ERAD 和 SelenoS-Se 如何影响 ERAD 复合物的结构和功能。