CARDIAC HYPERTROPHY--ROLE OF NUCLEAR T3 RECEPTORS

过量的甲状腺激素诱导一种独特形式的心脏肥大 其特征在于增强的心肌性能，这可能与 从低ATP酶形式的肌球蛋白转换为具有较高ATP酶的肌球蛋白 活动 目前，我们的实验室正试图确定 甲状腺激素调节肌球蛋白同工酶的机制 表情 虽然我们主要关注肌球蛋白的形成过程， 异构体转换，我们对缺乏有关 核甲状腺激素结合蛋白本身。 因此 这项研究的主要目的是研究核T3的作用， 受体在心肌肥厚的启动和控制中的作用 肌球蛋白同工酶表达。 为了实现这些目标，我们计划， 首先，通过使用以下技术克隆编码T3受体蛋白的cDNA 多克隆和单克隆抗体来鉴定编码这种蛋白的cDNA 在特别构建的Lambdagt11表达克隆库中的蛋白。 其次，我们建议确定特定的核DNA结合位点， T3受体。 我们已经开发了一种分离T3受体的策略， 其DNA片段连接并要求支持克隆， 对这些片段进行测序 这些结果将提供重要的新 与T3受体蛋白及其DNA结构相关的信息 结合位点。 这些调查将由一个合作机构进行， 莫金博士在图森的研究小组和基思博士莱瑟姆在 位于华盛顿的健康科学统一服务大学， 特区 莱瑟姆博士最近开发了多克隆和单克隆 受体蛋白的抗体。 我们相信我们组建的团队 对阐明甲状腺功能亢进的机制有重要意义 激素对心脏和其他组织的作用。

Excess thyroid hormone induces a unique form of cardiac hypertrophy characterized by enhanced myocardial performance which may be related to switching from a low ATPase form of myosin to one with higher ATPase activity. At present our laboratory is attempting to define the mechanism(s) by which thyroid hormone regulates myosin isoenzyme expression. Although we mainly are concerned with the process of myosin isoform switching, we are impressed with the lack of information about nuclear thyroid hormone binding proteins themselves. Accordingly, the major aim of the proposed research is to investigate the role of nuclear T3 receptor in the initiation of cardiac hypertrophy and in the control of myosin isoenzymes expression. To accomplish these objectives, we plan, first, to clone the cDNA coding for the T3 receptor protein by using polyclonal and monoclonal antibodies to identify cDNAs coding for this protein in a specially constructed Lambdagt11 expression clone bank. Secondly, we propose to identify specific nuclear DNA binding sites for the T3 receptor. We have developed a strategy for isolation of the T3 receptor with its DNA fragment attached and support is requested to clone and sequence these fragments. These results should provide significant new information related to the structure of the T3 receptor protein and its DNA binding sites. These investigations will be carried out by a collaboration between Dr. Morkin's group in Tucson and Dr. Keith Latham's laboratory at the Uniformed Services University of the Health Sciences in Washington, D.C. Dr. Latham recently has developed polyclonal and monoclonal antibodies to the receptor protein. We believe the team we have assembled can make significant progress on elucidation of the mechanism of thyroid hormone actions on the heart and in other tissues.