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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：
10322459
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322459
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.

项目总结