COFACTORS AND NUCLEAR HORMONE RECEPTOR FUNCTION

我们希望更好地了解核激素受体如何参与 正常细胞中的信号转导，以及在此过程中的病变， 导致疾病。核激素受体是转录因子， 调节基因表达以响应小的亲脂性配体，例如 类固醇甲状腺激素和类维生素A核激素受体 调节正常后生动物繁殖，增殖， 分化，和稳态;异常受体是致病因素， 多种人类内分泌和肿瘤疾病。 许多核激素受体表现出双峰转录特性， 并且可以抑制或激活基因表达。转录 在这些影响中，人们对抑制的了解最少。最近，我们和其他 已经鉴定了一个“共阻遏物”家族（不同引爆的TRAC， SMRT、N-CoR或RIP 13），与核激素物理相关 受体，并出现必要的转录沉默，这些 受体。我们的主要目标是确定这些合作伙伴的作用， 受体介导的基因调控中的阻遏物。具体而言：1.我们将 确定辅阻遏物如何与受体相互作用，以及 这种相互作用受到调节。2.我们将确定共抑制因子 与已知调节的其他调节途径的相互作用 受体功能3.我们还将阐明如何共同抑制， 与受体本身，与转录机制相互作用， 与染色质一起介导转录沉默。4.我们将确定 辅阻遏物在人类内分泌和肿瘤疾病中的作用。 作为次要目标，我们还将描述一系列额外的 核激素受体的潜在新效应物和/或调节剂 这是我们最近发现的。 这些实验的结果将有助于我们理解 激素受体功能背后的分子基础，在正常的 和患病的有机体。

We wish to better understand how nuclear hormone receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Nuclear hormone receptors are transcription factors that regulate gene expression in response to small lipophil ligands, such as steroids, thyroid hormones, and retinoids. Nuclear hormone receptors regulate key aspects of normal metazoan reproduction, proliferation, differentiation, and homeostasis; aberrant receptors are causal factors in a variety of human endocrine and neoplastic disorders. Many nuclear hormone receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. Transcriptional repression is least understood of these effects. Recently, we and other have identified a family of "co-repressors" (variously detonated TRACs, SMRT, N-CoR, or RIP13) that physically associate with nuclear hormone receptors and appear necessary for transcriptional silencing by these receptors. Our primary goal is to determine the roles of these co- repressors in receptor-mediated gene regulation. Specifically: 1. We will determine how co-repressors interact with receptors, and the manner in which the interaction is regulated. 2. We will determine how co-repressors interaction with other regulatory pathways that are know to modulate receptor function. 3. We will also elucidate how co-repressors, together with the receptor itself, interact with the transcriptional machinery and with chromatin to mediate transcriptional silencing. 4. We will determine the roles co-repressors play in human endocrine and neoplastic disorders. As a secondary goal we will also characterize an additional series of potentially novel effectors and/or modulators of nuclear hormone receptor action that we have recently identified. The results from these experiments will contribute to our understanding of the molecular basis behind hormone receptor function in both the normal and the diseased organism.