Chemical Biology of Nuclear Receptor Action in the Macrophage

描述(申请人提供)：肥胖是美国的一个主要健康问题。它增加了胰岛素抵抗(IR)和代谢综合征(MS)的风险，这是一系列心血管疾病(CVD)的危险因素，并导致其他病理因素，包括非酒精性脂肪性肝炎(NASH)，这是导致肝硬变的第二大最常见原因；阿尔茨海默病；心肌病；癌症；以及其他许多与衰老有关或因衰老而加剧的疾病。原则上，通过改变生活方式(饮食和锻炼)来治疗和预防肥胖应该是简单的，但这些方法并不奏效。因此，开发治疗肥胖症和胰岛素抵抗的创新疗法至关重要。在过去的十年中，肥胖/IR与低度全身炎症有关，脂肪组织巨噬细胞(ATM)的极化状态是这些看似不同的现象之间的重要联系。ML促炎巨噬细胞分泌抑制局部和全身胰岛素信号的因子，而交替激活的M2巨噬细胞对抗ML巨噬细胞的促炎作用，增强胰岛素敏感性，减轻高脂饮食的有害影响。最近的数据表明，三种核受体(NRs)在M2巨噬细胞表型的形成中起重要作用，即PPARs y和6以及雌激素受体a(Era)。此外，巨噬细胞中还表达至少20种NRs，这些NRs在巨噬细胞中的激活作用尚不清楚。在这项提案中，我们将组建一个团队来了解选择性地操纵自动取款机中的NR信号以抑制代谢性疾病同时避免NR配体对身体的典型有害副作用的最佳方法。我们的团队汇集了来自不同机构的科学家，他们是代谢疾病和巨噬细胞动物模型中NR作用、NR结构和分子生物学、NR作用的化学生物学、NR基因组和天然NR配体方面的专家。我们相信，这个团队将能够很好地定义针对巨噬细胞NRs的方法，并开发新的配体来选择性地操纵这种细胞类型的NR信号，并且R24机制将完美地帮助我们形成一个专注于巨噬细胞中NR作用的化学生物学的团队。 相关性：核受体是一个重要的蛋白质家族，是药物开发的既定靶点。目前美国有20%的处方是针对核受体配体的。调节巨噬细胞中NRs活动的药物可以对抗炎症，这些炎症导致胰岛素抵抗、肥胖和代谢综合征的其他方面，而代谢综合征是当今美国面临的最大健康问题之一。

DESCRIPTION (provided by applicant): Obesity is a major health problem in the United States. It increases the risk of insulin resistance (IR) and metabolic syndrome (MS), a cluster of cardiovascular disease (CVD) risk factors, and leads to additional pathologies, including non-alcoholic steatohepatitis (NASH), the second most common cause of liver cirrhosis; Alzheimer's disease; cardiomyopathy; cancer; and others, many associated with or exacerbated by aging. In principle, it should be simple to treat and prevent obesity with lifestyle modifications (diet and exercise) but these approaches have not worked well. It is therefore essential to develop innovative treatments for obesity and IR. Over the last ten years, it has become clear that obesity/IR is related to low- grade systemic inflammation and that the polarization state of adipose tissue macrophages (ATMs) is the important link between these seemingly disparate phenomena. Ml pro-inflammatory macrophages secrete factors that inhibit local and systemic insulin signaling whereas alternatively activated M2 macrophages counter the pro-inflammatory actions of Ml macrophages and enhance insulin sensitivity and blunt harmful effects of high fat diet. Recent data indicates that three nuclear receptors (NRs) are important for elaboration of M2 macrophage phenotype, peroxisome proliferator activated receptors (PPARs) y and 6 and estrogen receptor a (ERa). In addition, at least 20 other NRs are expressed in macrophages and effects of activation of these NRs in macrophage are unknown. In this proposal, we will assemble a team to understand the best way to selectively manipulate NR signaling in ATMs to inhibit metabolic disease while avoiding typical harmful side effects of NR ligands on the body. Our team brings together scientists from different institutions who are experts in NR actions in animal models of metabolic disease and macrophages, NR structure and molecular biology, chemical biology of NR action and NR genomics and natural NR ligands. We believe that this team will be well equipped to define ways to target macrophage NRs and develop new ligands to selectively manipulate NR signaling in this cell type and that the R24 mechanism will be perfect to help us form a team with a strong focus on chemical biology of NR action in macrophage. RELEVANCE: The nuclear receptors are an important protein family that is a well established target for drug development. 20% of current US prescriptions are for nuclear receptor ligands. Drugs that modulate activities of NRs in the macrophage could combat inflammation that contributes to insulin resistance, obesity and other aspects of metabolic syndrome, one of the biggest health problems facing the United States today.