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Thyroid Hormone Receptor Function in Cardiac Hypertrophy

甲状腺激素受体在心脏肥大中的功能

基本信息

批准号：
7023834
负责人：
Kaie Margareeta OJAMAA
金额：
$ 35.33万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-28 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many aspects of cardiac contractile function are determined by the action of thyroid hormones, specifically triiodothyronine (T3), on myocyte-specific gene transcription that is mediated byT3 binding to one or more nuclear thyroid hormone receptors (TR). The precise role of the individual TRs (TR alpha I,TR beta 1) and their post-transcriptional modification in determining transcription of specific cardiomyocyte genes, including co-myosin heavy chain (alpha-MHC), remains unknown. The myocardium in conditions of pathologic and physiologic hypertrophy exhibits altered expression of many T3-responsive genes, which can be partially normalized by T3 treatment. The present application will test the hypothesis that impaired T3 responsiveness in the hypertrophied heart is the result of altered expression and phosphorylation of TR isoforms which affect all aspects of nuclear receptor function including DNA binding, dimerization, interaction with co-regulators, ligand affinity and transcriptional activity. In the first two specific aims, we propose to test the hypothesis that the hypertrophic cardiac phenotype is a result of changes in nuclear, content of TR isoforms and that the individual TR alpha I and beta 1 isoforms are differentially phosphorylated as assessed by isolation of nuclear proteins from purified adult rat ventricular myocytes. Our preliminary data suggest that the non-T3 binding isoform, TR alpha 2,has the unique ability to repress T3-inducible transcription of cardiac alpha-MHC and SERCA2 genes. A recombinant adenovirus strategy will be used in specific aim 3 to overexpress TR alpha 2 protein in cultured cardiomyocytes,and the resulting changes in transcription of the endogenous alpha-MHC gene will be measured by a novel assay to quantify alpha-MHC heteronuclear RNA. Specific aim 4 will test will the hypothesis that protein kinase C signaling pathways that are activated in the hypertrophic myocardium result in phosphorylation of specific TR isoforms, which in turn mediate changes in cardiac phenotype remarkably similar to that of the hypothyroid heart. We will study the effects of adenoviral-mediated overexpression of individual PKC delta, epsilon, and zeta isoenzymes on specific TR isoform phosphorylation and alpha-MHC gene transcription. Completion of these studies will provide novel mechanistic information regarding the role of TRs in mediating the hypertrophic phenotype, and provide the rationale for the potential therapeutic utility of T3 in the setting of congestive heart failure.

描述（由申请人提供）：心脏收缩功能的许多方面是由甲状腺激素，特别是三碘甲状腺原氨酸（T3）对肌细胞特异性基因转录的作用决定的，该基因转录是由T3与一个或多个核甲状腺激素受体（TR）结合介导的。个体TRs （TR α 1,TR β 1）及其转录后修饰在决定特定心肌细胞基因转录中的确切作用，包括共肌球蛋白重链（α - mhc），目前尚不清楚。病理性和生理性肥大的心肌表现出许多T3应答基因的表达改变，这可以通过T3治疗部分正常化。本应用程序将验证肥大心脏中T3反应性受损是TR异构体表达和磷酸化改变的结果，其影响核受体功能的各个方面，包括DNA结合、二聚化、与共调节因子的相互作用、配体亲和力和转录活性。在前两个特定目的中，我们提出验证以下假设：肥厚型心脏表型是TR同工型核含量变化的结果，通过从纯化的成年大鼠心室肌细胞中分离核蛋白来评估单个TR α 1和β 1同工型的差异磷酸化。我们的初步数据表明，非t3结合异构体TR α 2具有抑制t3诱导的心脏α - mhc和SERCA2基因转录的独特能力。重组腺病毒策略将用于特异性靶3，在培养的心肌细胞中过表达TR α 2蛋白，并通过一种新的测定α - mhc异核RNA的方法来测量内源性α - mhc基因转录的变化。特异性目标4将验证在肥厚心肌中激活的蛋白激酶C信号通路导致特定TR亚型磷酸化的假设，这反过来介导了与甲状腺功能低下心脏非常相似的心脏表型变化。我们将研究腺病毒介导的PKC δ、epsilon和zeta同工酶过表达对特异性TR异构体磷酸化和α - mhc基因转录的影响。这些研究的完成将为TRs介导肥厚表型的作用提供新的机制信息，并为T3在充血性心力衰竭中的潜在治疗效用提供理论依据。