Insulin Signaling in Tissue Resident Macrophages

组织驻留巨噬细胞中的胰岛素信号转导

• 批准号: 9467946
• 负责人: Jessica Jane Ye
• 金额: $ 2.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467946
• 关键词: Adipocytes; Affect; Agonist; Anabolism; Apoptotic; Architecture; Area; Asthma; Atherosclerosis; Behavior; Biology; Bone Marrow; Cells; Clinical; Comorbidity; Cues; Data; Diabetes Mellitus; Disease; Eating; Endocrine; Endocrinology; Event; Fasting; Fibroblasts; Genetic Transcription; Growth; Growth Factor; Heart Diseases; Hepatocyte; High Fat Diet; Hormonal; Hormones; Hypersensitivity; Hypoxia; IRS2 gene; Immune; Immunology; Immunoprecipitation; In Vitro; Inflammation; Insulin; Insulin Receptor; Insulin Signaling Pathway; Insulin-Like-Growth Factor I Receptor; Interleukin 4 Receptor; Interleukin-4; Knockout Mice; Learning; Light; Logic; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Mus; Muscle Fibers; Obesity; Obesity associated cancer; PPAR gamma; Pathogenesis; Pathway interactions; Phosphatidylinositols; Phosphoproteins; Phosphorylation; Phosphotransferases; Physiological; Physiology; Play; Population; Positioning Attribute; Prevention; Process; Punch Biopsy; Receptor Signaling; Recruitment Activity; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Stress; Surface; Testing; Tissues; Wound Healing; angiogenesis; base; blood glucose regulation; cell type; cost; cross reactivity; diabetes risk; diabetic; experimental study; feeding; improved; insulin signaling; interest; macrophage; novel diagnostics; novel therapeutics; pathogen; receptor; receptor expression; response; rosiglitazone; scaffold; sensor; skin disorder; tissue repair; trait

7. Project Summary / Abstract Insulin is a key metabolic hormone and growth factor best known for its role in glucose homeostasis. Because responses to insulin are frequently dysregulated in metabolic disease, the relevant signaling pathways in parenchymal cells of metabolic tissues (adipocytes, skeletal myocytes, and hepatocytes) have been extensively characterized. In contrast, insulin signaling in other cell types, such as tissue resident macrophages, is much less clear. However, given the pivotal role of resident macrophages in tissue function and physiology, as well as in the pathogenesis of metabolic disease, it is important to understand how insulin affects their behavior and function. In this project we plan to explore how insulin, a reliable indicator of food intake, signals to macrophages and affects their polarization according to different needs in the fed or fasted state. Preliminary experiments suggest insulin signaling in macrophages is different from that in metabolic tissues. Most strikingly, there is an apparent lack of downstream signaling upon in vitro stimulation of macrophages with physiological concentrations of insulin, despite robust expression of the receptor. In the first aim, we plan to study the mechanistic basis of this observation, and how changes in signaling architectures may sensitize macrophages to insulin signaling, which we have observed. The role of insulin signaling in macrophages has been studied in the context of various disease processes. However, a clear logic to the effects of insulin signaling remains elusive. Furthermore, many studies are confounded by the use of supraphysiological concentrations of insulin, which may cause cross reactivity with other receptors such as the insulin-like growth factor 1 receptor, also expressed by macrophages, or other nonspecific surface receptors. Some preliminary data suggest insulin may have an effect on macrophage alternative activation in response to interleukin 4. To further define the role of insulin signaling in macrophages in relation to tissue function, in the second aim I plan to assess how insulin may affect M2 polarization and wound healing.

7. 项目总结/摘要 胰岛素是一种关键的代谢激素和生长因子，以其在葡萄糖稳态中的作用而闻名。因为 在代谢疾病中，对胰岛素的反应经常失调，相关信号通路 代谢组织的实质细胞（脂肪细胞、骨骼肌细胞和肝细胞） 广泛表征。相比之下，其他细胞类型（例如组织驻留细胞）中的胰岛素信号传导 巨噬细胞，还不太清楚。然而，考虑到常驻巨噬细胞在组织功能中的关键作用 和生理学以及代谢疾病的发病机制中，了解胰岛素如何发挥作用非常重要 影响他们的行为和功能。在这个项目中，我们计划探索胰岛素这一可靠的指标如何 食物摄入量，向巨噬细胞发出信号，并根据不同的需要影响它们的极化 进食或禁食状态。初步实验表明巨噬细胞中的胰岛素信号传导与此不同 在代谢组织中。最引人注目的是，体外实验明显缺乏下游信号传导。 尽管胰岛素的强烈表达，但用生理浓度的胰岛素刺激巨噬细胞 受体。第一个目标是，我们计划研究这一观察结果的机制基础，以及如何变化 我们已经观察到，信号结构中的信号通路可能会使巨噬细胞对胰岛素信号敏感。 巨噬细胞中胰岛素信号传导的作用已在各种疾病过程的背景下进行了研究。 然而，胰岛素信号传导影响的清晰逻辑仍然难以捉摸。此外，许多研究都是 因使用超生理浓度的胰岛素而感到困惑，这可能会导致与胰岛素的交叉反应 其他受体，例如胰岛素样生长因子 1 受体，也由巨噬细胞或其他细胞表达 非特异性表面受体。一些初步数据表明胰岛素可能对巨噬细胞有影响 响应白细胞介素的替代激活 4. 进一步明确胰岛素信号传导在 巨噬细胞与组织功能的关系，在第二个目标中，我计划评估胰岛素如何影响 M2 极化和伤口愈合。