Chemical Biology of Nuclear Receptor Action in the Macrophage

巨噬细胞核受体作用的化学生物学

• 批准号: 7868719
• 负责人: Willa A Hsueh
• 金额: $ 48.86万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7868719
• 关键词: Adipose tissue; Adverse effects; Aging; Alzheimer' s Disease; Animal Model; Behavior Therapy; Biology; Cardiomyopathies; Chemicals; Data; Diet; Estrogen Receptors; Fatty acid glycerol esters; Genomics; Health; Inflammation; Inflammatory; Institution; Insulin Resistance; Ligands; Link; Liver Cirrhosis; Malignant Neoplasms; Metabolic Diseases; Metabolic syndrome; Molecular Biology; Monoclonal Antibody R24; Nuclear Receptors; Obesity; Pathology; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Protein Family; Receptor Signaling; Risk; Risk Factors; Scientist; Structure; United States; Work; cardiovascular disorder risk; cell type; combat; diet and exercise; drug development; innovation; insulin sensitivity; insulin signaling; macrophage; nonalcoholic steatohepatitis; obesity treatment; prevent

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.

描述（由申请人提供）：肥胖是美国的一个主要健康问题。它会增加胰岛素抵抗 (IR) 和代谢综合征 (MS) 等一系列心血管疾病 (CVD) 危险因素的风险，并导致其他病变，包括非酒精性脂肪性肝炎 (NASH)，这是导致肝脏疾病的第二常见原因肝硬化;阿尔茨海默病；心肌病;癌症;以及其他一些疾病，其中许多与衰老有关或因衰老而加剧。原则上，通过改变生活方式（饮食和运动）来治疗和预防肥胖应该很简单，但这些方法效果不佳。因此，开发针对肥胖和 IR 的创新疗法至关重要。在过去的十年中，人们已经清楚肥胖/IR与低度全身炎症有关，并且脂肪组织巨噬细胞（ATM）的极化状态是这些看似不同的现象之间的重要联系。 M1促炎巨噬细胞分泌抑制局部和全身胰岛素信号传导的因子，而替代激活的M2巨噬细胞对抗M1巨噬细胞的促炎作用并增强胰岛素敏感性并减弱高脂肪饮食的有害影响。最近的数据表明，三种核受体 (NR)、过氧化物酶体增殖物激活受体 (PPAR) y 和 6 以及雌激素受体 a (ERa) 对于 M2 巨噬细胞表型的形成非常重要。此外，至少有 20 种其他 NR 在巨噬细胞中表达，并且这些 NR 在巨噬细胞中的激活作用尚不清楚。在本提案中，我们将组建一个团队来了解选择性操纵 ATM 中 NR 信号传导以抑制代谢疾病的最佳方法，同时避免 NR 配体对身体产生典型的有害副作用。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的 NR 作用、NR 结构和分子生物学、NR 作用的化学生物学以及 NR 基因组学和天然 NR 配体方面的专家。我们相信，该团队将有能力定义靶向巨噬细胞 NR 的方法，并开发新的配体来选择性操纵该细胞类型中的 NR 信号传导，并且 R24 机制将非常完美，可以帮助我们组建一支专注于化学生物学的团队巨噬细胞中的 NR 作用。 相关性：核受体是一个重要的蛋白质家族，是药物开发的既定目标。目前美国 20% 的处方是针对核受体配体的。调节巨噬细胞中 NR 活性的药物可以对抗导致胰岛素抵抗、肥胖和代谢综合征其他方面的炎症，代谢综合征是当今美国面临的最大健康问题之一。