The Mechanism of Transcriptional Repression by Hairless

描述(申请人提供)：在人类中，围产期甲状腺激素(TH)缺乏会导致神经系统发育缺陷，包括智力低下。TH通过结合核受体发挥作用，核受体可以控制基因转录。因此，TH通过诱导TH反应基因来调节发育。无毛(Hair less，HR)是一种在大脑中表达的TH反应基因，因此可能参与神经系统的直接发育。我们的实验室最近将HR的生化功能定义为一种可以通过TRR发挥作用的辅阻遏子。辅阻遏物是一种可以通过DNA结合转录因子抑制转录的蛋白质。因此，该蛋白的生化特征表明，HR可能参与了TR的转录作用机制。这项研究的目的是探讨基于HR的转录抑制的机制，因为这将使我们更好地理解TR是如何发挥转录调节作用的，以及TR是如何通过招募HR来影响神经系统发育的。我将从三个方面研究基于HR的抑制：1)确定每个抑制结构域在基于HR的抑制中的作用；2)识别HR抑制结构域招募的蛋白质；3)证明HR相互作用蛋白参与基于HR的抑制。通过弄清HR介导的转录抑制的分子机制，我们可能会发现治疗设计的新途径，以对抗由于基因表达改变而导致的智力低下。

DESCRIPTION (provided by applicant): In humans, perinatal thyroid hormone (TH) deficiency results in developmental defects that in the nervous system includes mental retardation. TH acts through binding nuclear receptors (TR), which can control gene transcription. Thus, TH regulates development through induction of TH-responsive genes. hairless (hr) has been identified as a TH-responsive gene expressed in the brain, and thus is potentially involved in TH directed development of the nervous system.Our lab has recently defined the biochemical function of Hr as a corepressor that can act through TR. Corepressors are proteins that can repress transcription via a DNA bound transcription factor. Thus, the biochemical characterization of the protein has revealed that Hr may be involved in the mechanism of TR's transcriptional action. The purpose of the proposed research is to investigate the mechanism of Hr-based transcriptional repression, as this will lead to a greater understanding of how TR functions as a transcriptional regulator and how TR, through the recruitment of Hr, may affect nervous system development. I shall investigate Hr-based repression in three ways: 1) Determine the role of each of the repression domains in Hr-based repression; 2) Identify proteins that are recruited by Hr repression domains; 3) Demonstrate that the Hr-interacting protein is involved in Hr-based repression. By discerning the molecular mechanisms of Hr-mediated transcriptional repression, we may discover new avenues for therapeutic design to combat mental retardation as a consequence of altered gene expression.