A ROLE FOR SELENOPROTEINS IN CARDIAC DISEASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 硒(Se)是一种必需的营养物质，可以保护心脏组织免受在各种心脏疾病中发生的氧化损伤。硒直接结合到硒蛋白家族的成员中，作为氨基酸，硒半胱氨酸。到目前为止，已鉴定出25种硒蛋白，但其中许多蛋白的功能，特别是在心脏中的功能，尚未确定。本项目的目的是利用几种不同的心脏病理学小鼠模型来确定参与保护心脏组织免受损伤的硒蛋白，并确定去除硒蛋白合成如何影响不同的心脏疾病。我们的中心假设是，特定的硒蛋白发挥重要的保护作用，并将在这些疾病的发病过程中上调，而涉及最高水平的氧化应激的心脏疾病在心脏组织中硒蛋白合成被去除的小鼠中将更加严重。我们计划实现以下具体目标：1)确定在心脏组织中表达的硒蛋白，并确定在各种心脏疾病的背景下如何调节表达；以及2)确定去除硒蛋白合成如何影响不同类型的心脏疾病。对于特定的目标1，将进行四种不同的心肌病小鼠模型，这些模型适用于人类疾病。这些包括阿霉素引起的心脏毒性、糖尿病、缺血再灌注和衰老小鼠。这些小鼠的心脏组织将被分析所有硒蛋白家族成员的水平以及参与其合成的因素，包括mRNA丰度、蛋白质表达和心脏组织中蛋白质表达的定位。对于特定目的2，一种已建立的loxP-Cre技术将被用来移除编码对硒蛋白合成至关重要的硒环状花柱tRNA的基因trsp。在心血管发育完成后，这个基因将在出生时在心脏组织中被切除。上面列出的小鼠模型将在这些小鼠身上进行，然后将分析疾病进展以及组织病理学、组织坏死、心功能和氧化应激标志物所指示的心脏病理水平。该项目的完成将对硒蛋白在心脏疾病中所起的作用提供有价值的见解，并可能导致更好的预测性和个体化治疗方式，涉及硒和心脏病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selenium (Se) is an essential nutrient that protects cardiac tissue from oxidative damage occurring during a variety of cardiac disorders. Se is directly incorporated into members of the selenoprotein family as the amino acid, selenocysteine. To date 25 selenoproteins have been identified, but the function of many of these proteins, particularly in the heart, have yet to be determined. The objective of this project is to employ several different mouse models of cardiopathology to identify selenoproteins involved in protecting heart tissue from injury and to determine how the ablation of selenoprotein synthesis affects different cardiac disorders. Our central hypothesis is that particular selenoproteins play important protective roles and will be upregulated during onset of these disorders, and that cardiac disorders that involve the highest levels of oxidative stress will be more severe in mice with ablated selenoprotein synthesis in heart tissue. We plan to carry out the following specific aims: 1) Identify selenoproteins that are expressed in cardiac tissues and determine how expression is regulated in the setting of a variety of cardiac diseases; and 2) Determine how ablation of selenoprotein synthesis affects different types of cardiac diseases. For Specific Aim 1, four different mouse models of cardiomyopathy will be conducted that have applicability to human diseases. These include adriamycin-induced cardiotoxicity, diabetes, ischemia-reperfusion, and aging mice. Cardiac tissues from these mice will be analyzed for levels of all selenoprotein family members as well as factors involved in their synthesis in terms of mRNA abundance, protein expression, and localization of protein expression within cardiac tissue. For Specific Aim 2, an established LoxP-Cre technique will be used to remove a gene, trsp, that encodes the selenocystyl-tRNA crucial for selenoprotein synthesis. This gene will be excised in cardiac tissue at birth, after cardiovascular development is complete. The mouse models listed above will be carried out on these mice, which will then be analyzed for disease progression as well as levels of cardiopathology indicated by histological pathology, tissue necrosis, ventricular function, and markers of oxidative stress. Completion of this project will provide valuable insight into the role that selenoproteins play in cadiac disorders and may lead to better predictive and personal treatment modalities involving Se and cardiac diseases.