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

项目摘要 许多形式的心血管疾病导致病理性心脏肥大，这是适应不良的， 它会导致心脏收缩力降低，导致危及生命的心力衰竭。相反，锻炼可以 导致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 长期目标是更好地理解心脏生长的两种形式。在这一提议中， 我们将通过研究硒在心肌肥大中的作用来阐明这一认识。Se，这是 我们饮食中的一种基本元素，众所周知是心血管健康所必需的，尽管确切的作用 由硒发挥的心血管系统是未知的。硒在所有器官和细胞中的一个主要作用是， 硒是硒蛋白的关键成分;在这里，我们将研究硒在心脏硒蛋白中的功能。我们 具体的目标是检查硒蛋白，SelenoS，我们认为这是需要的， 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和特异性地损害或增强心脏肥大， SelenoS的功能，然后进行研究，以确定这些演习对心脏结构的影响， 功能我们将讨论的一个机制点是硒如何影响心脏生长。然而，由于有 23其他蛋白质在小鼠中需要硒，为了集中我们的方法来确定硒是如何使用的，只有 硒在心脏中的作用，我们将研究硒的突变形式，硒硒，这是不同的 只因为它没有硒。通过这种方式，我们将能够机械地查明Se 只有SelenoS才能支持心脏生长，因为所有其他硒蛋白仍然含有硒。 融入他们的结构。SelenoS还参与了细胞中错误折叠蛋白质的适应性降解。 内质网，一个叫做ERAD的过程。我们还将研究硒，硒-硒， 和一种不能在ERAD中起作用的硒形式，硒-ERAD，对心脏生长。我们的具体目标是 1-测定内源性硒耗竭对心脏结构、功能、基因和蛋白质的影响 在小鼠心脏肥大模型中的表达，2-检查SelenoS异位表达的影响， 在小鼠中，内源性硒已经被敲低，在病理学上， 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。

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.