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，心血管疾病（CVD）危险因素簇，并导致其他病理，包括非酒精性脂肪性肝炎（NASH），第二大最常见的肝脏原因肝硬化；阿尔茨海默氏病；心肌病；癌症;还有其他，许多与衰老有关或加剧的。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，但是这些方法效果不佳。因此，为肥胖和IR开发创新治疗至关重要。在过去的十年中，很明显肥胖/IR与低年级的全身性炎症有关，并且脂肪组织巨噬细胞（ATM）的极化状态是这些看似截然不同的现象之间的重要联系。 ML促炎性巨噬细胞分泌抑制局部和全身胰岛素信号传导的因素，而替代激活的M2巨噬细胞应对ML巨噬细胞的促炎作用，并增强胰岛素敏感性和高脂肪饮食的有害作用。最近的数据表明，三个核受体（NR）对于阐述M2巨噬细胞表型，过氧化物酶体增殖物激活受体（PPARS）Y和6以及雌激素受体A（ERA）很重要。另外，在巨噬细胞中至少表达了至少20个其他NR，并且这些NR在巨噬细胞中激活的影响尚不清楚。在此提案中，我们将组建一个团队，以了解ATM中选择性操纵NR信号的最佳方法，以抑制代谢性疾病，同时避免NR配体对体内的典型有害副作用。我们的团队汇集了来自不同机构的科学家，这些科学家是代谢疾病和巨噬细胞动物模型，NR结构和分子生物学，NR作用和NR基因组学和天然NR配体的化学生物学的专家。我们认为，该团队将有能力定义瞄准巨噬细胞NRS并开发新的配体以选择性操纵这种细胞类型中的NR信号的方法，R24机制将是完美的，可以帮助我们组建一支对化学生物学专注的团队巨噬细胞中的NR作用。 相关性：核受体是重要的蛋白质家族，是药物开发的良好靶标。当前美国处方的20％用于核受体配体。调节NRS在巨噬细胞中活性的药物可能会抗击炎症，从而导致胰岛素抵抗，肥胖和代谢综合征的其他方面，这是当今美国面临的最大健康问题之一。