A ROLE FOR SELENOPROTEINS IN CARDIAC DISEASES

硒蛋白在心脏病中的作用

• 批准号: 8167743
• 负责人: PETER R HOFFMANN
• 金额: $ 23.59万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167743
• 关键词: Ablation; Adriamycin PFS; Affect; Aging; Amino Acids; Birth; Cardiac; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Computer Retrieval of Information on Scientific Projects Database; Development; Diabetes Mellitus; Disease; Disease Progression; Family; Family member; Funding; Genes; Grant; Heart; Heart Diseases; Injury; Institution; Ischemia; Lead; Messenger RNA; Modality; Mus; Necrosis; Nutrient; Onset of illness; Oxidative Stress; Pathology; Play; Proteins; Reperfusion Therapy; Research; Research Personnel; Resources; Role; Selenium; Selenocysteine; Source; Techniques; Tissues; Transfer RNA; United States National Institutes of Health; Ventricular Function; human disease; insight; member; mouse model; oxidative damage; protein expression; selenoprotein

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 硒（Se）是一种必需的营养素，可保护心脏组织免受各种心脏疾病期间发生的氧化损伤。硒以氨基酸硒代半胱氨酸的形式直接结合到硒蛋白家族的成员中。到目前为止，已经鉴定了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。本项目的目的是采用几种不同的小鼠心脏病理模型，以确定硒蛋白参与保护心脏组织免受损伤，并确定硒蛋白合成的消融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，心脏疾病，涉及最高水平的氧化应激将更严重的小鼠与消融硒蛋白合成在心脏组织。我们计划实现以下具体目标：1）鉴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; 2）确定硒蛋白合成的消融如何影响不同类型的心脏疾病。对于特定目标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。这些包括阿霉素诱导的心脏毒性、糖尿病、缺血再灌注和衰老小鼠。将分析来自这些小鼠的心脏组织的所有硒蛋白家族成员的水平以及在mRNA丰度、蛋白质表达和心脏组织内蛋白质表达的定位方面参与其合成的因素。对于特定目标2，将使用已建立的LoxP-Cre技术来去除编码对硒蛋白合成至关重要的硒代胱氨酸-tRNA的基因trsp。这种基因将在出生时心血管发育完成后在心脏组织中被切除。将对这些小鼠进行上述小鼠模型，然后分析疾病进展以及由组织病理学、组织坏死、心室功能和氧化应激标志物指示的心脏病理学水平。该项目的完成将为硒蛋白在心脏疾病中的作用提供有价值的见解，并可能导致更好的预测和个人治疗方式，涉及硒和心脏疾病。