This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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