MLL3/4-complexes in nuclear receptor-mediated metabolism

描述(由申请人提供)：这是前一项工作的更新建议，题为“核受体辅活化子ASC-2的调节代码”。这项研究的目的是确定ASC-2及其稳态复合体ASCOM(对于ASC-2复合体)在核受体(NR)反式激活中的作用。在这项研究过程中，我们有了一个新的发现，即Ascom在新陈代谢中起着至关重要的作用。这包括脂肪和葡萄糖的动态平衡，这是代谢综合征的两个重要方面。重要的是，可能导致这场快速增长的大流行的代谢转录调控尚不清楚。因此，ASCOM直接参与代谢综合征的这一令人兴奋的新可能性证明了当前提议的力量。这项研究的潜在创新性也从ASCOM含有酶的事实中可见一斑，这些酶可以作为开发治疗代谢综合征的药物的新靶点。这项研究的主要假设是Ascom是一个共激活复合体，专用于至少一个参与新陈代谢的NRs子集。具体地说，我们将确定1)Ascom关键成分在NR反式激活过程中的生化和分子功能，这是先前目标的延续；2)Ascom在脂和糖代谢中的作用，这是基于Ascom代谢功能的一个新的研究领域。值得注意的是，这是一项综合良好的研究，因为研究的第一部分对于在研究的第二部分了解ASCOM代谢功能的分子基础是必不可少的。这两个关键问题将在三个具体目标中解决，这三个目标利用生化、细胞和遗传方法的集合。在目标1中，我们将定义Ascom调节NR反式激活的分子机制。在目标2中，我们将确定Ascom在肝脏X受体(LXR)反式激活中的作用。在目标3中，我们将确定Ascom在法尼类X受体(FXR)反式激活中的肝脏功能。总之，这项研究将有助于理解NRs调控转录、控制新陈代谢和能量稳态的分子机制。公共卫生相关性：我们发现ASCOM在核受体调控代谢基因的复杂网络中发挥核心作用。因此，对ASCOM的研究将直接有助于我们理解核受体对代谢的控制。此外，这项研究可以直接应用于设计适当的策略来对抗代谢综合征，这是一种日益严重的流行病，因为ASCOM有两种不同类别的化学顺应酶。

DESCRIPTION (provided by applicant): This is a renewal proposal for the previous work, entitled "Regulation Code by Nuclear Receptor Coactivator ASC-2". This previous study's goal was to define the roles for ASC-2 and its steady-state complex ASCOM (for ASC-2-COMplex) in nuclear receptor (NR) transactivation. During the course of this study, we made the novel finding that ASCOM plays crucial roles in metabolism. This includes lipid and glucose homeostasis, two key areas which are important for the metabolic syndrome. Importantly, the metabolic transcriptional regulation that can lead to this rapidly growing pandemic remains unclear. Therefore, this exciting new possibility for ASCOM to be directly involved with the metabolic syndrome attests the strength of the current proposal. The potential innovativeness of this study is also evident from the fact that ASCOM contains enzymes, which can serve as new targets for developing drugs to treat the metabolic syndrome. The major hypothesis of this study is that ASCOM is a coactivator complex specialized for at least a subset of NRs involved with metabolism. Specifically, we will determine 1) the biochemical and molecular function of key constituents of ASCOM during NR transactivation, which is a continuation of the previous aims, and 2) the role for ASCOM in lipid and glucose metabolism, which represents a newly focused area of study based on the metabolic function of ASCOM. It is important to note that this is a well-integrated study, because the first part of the study is essential to understand the molecular basis for the metabolic function of ASCOM in the second part of the study. These two critical issues will be addressed in three specific aims, which utilize an ensemble of biochemical, cellular and genetic approaches. In Aim 1, we will define the molecular mechanisms by which ASCOM regulates NR transactivation. In Aim 2, we will define the hepatic roles for ASCOM in liver X receptor (LXR) transactivation. In Aim 3, we will define the hepatic function for ASCOM in farnesoid X receptor (FXR) transactivation. Overall, this study will help understand the molecular mechanisms by which NRs regulate transcription and control metabolism and energy homeostasis. PUBLIC HEALTH RELEVANCE: We found that ASCOM plays central roles in a complex network of metabolic gene regulation by nuclear receptors. Thus, this study of ASCOM will directly contribute to our understanding of metabolic control by nuclear receptors. Moreover, this study can be directly applied to designing proper strategies to fight against the metabolic syndrome, a growing pandemic, because ASCOM has two distinct classes of chemically amenable enzymes.