CARDIAC HYPERTROPHY--ROLE OF NUCLEAR T3 RECEPTORS

过量的甲状腺激素导致一种独特的心肌肥厚 以心肌功能增强为特征，这可能与 从低ATPase形式的肌球蛋白转换为高ATPase形式的肌球蛋白 活动。目前，我们实验室正在尝试定义 甲状腺激素调节肌球蛋白同工酶的机制(S) 表情。虽然我们主要关注肌球蛋白的过程 Isoform Switch，我们对缺乏关于 核甲状腺激素结合蛋白本身。因此， 这项拟议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调控中的作用 肌球蛋白同工酶的表达。为了实现这些目标，我们计划， 首先，克隆编码T3受体蛋白的c DNA。 多克隆和单克隆抗体用于鉴定编码该基因的cDNA 在特制的Lambdagt11表达克隆文库中表达蛋白质。 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 附上其DNA片段，并需要支持才能克隆和 对这些碎片进行排序。这些结果应该会提供重要的新的 与T3受体蛋白及其DNA结构有关的信息 结合部位。这些调查将通过合作进行 在图森的Morkin博士团队和Keith Latham博士的实验室之间 华盛顿健康科学统一服务大学， D.C.莱瑟姆博士最近研制出了多克隆和单克隆 针对受体蛋白的抗体。我们相信我们组建的团队 可以在阐明甲状腺的机制方面取得重大进展 荷尔蒙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.