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Pentraxin regulation of macrophage differentiation

Pentraxin对巨噬细胞分化的调节

基本信息

批准号：
9247823
负责人：
Richard H Gomer
金额：
$ 35.02万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247823
关键词：
Affect Amyloid Animal Model Asthma Atherosclerosis Autoimmune Diseases Binding Biological Assay Blood Cells Chronic Data Disease Disease Progression Environment Family Fc Receptor Fibrosis Goals Human Immune system Immunoglobulin G Infection Inflammation Inflammatory Injection of therapeutic agent Innate Immune System Knockout Mice Lead Leishmania Ligand Binding Ligands Malignant Neoplasms Mediating Modeling Molecular Mus Nomenclature Obesity PTX3 protein Phenotype Plasma Plasma Proteins Play Polysaccharides Preclinical Drug Evaluation Production Property Protein Family Proteins Regulation Resistance Resolution Role Serum Serum Proteins Signal Transduction Signaling Protein Small Interfering RNA Surface System Testing Therapeutic Tuberculosis Work cytokine drug candidate functional outcomes high risk immunoregulation inflammatory marker insight knock-down macrophage member monocyte novel novel therapeutics pathogen public health relevance receptor repaired response small molecule tissue repair

项目摘要

DESCRIPTION (provided by applicant): Macrophages play a major role in diseases such as tuberculosis, Leishmania, chronic inflammation, autoimmune diseases, atherosclerosis, obesity, asthma, fibrosis, and cancer, and the disease progression is strongly affected by whether the macrophages are inflammatory M1, profibrotic M2a, or immunoregulatory M2reg. The differentiation of monocytes into M1, M2a, or M2reg has been thought to occur in response to signals released during inflammation or repair. Unexpectedly, a constitutive blood plasma protein called Serum Amyloid P (SAP) induces monocytes to become M2reg macrophages. Signals inducing and produced by M2a macrophages are associated with fibrosis. Injections of SAP in animal models of fibrosis override these signals, induce M2reg differentiation, and inhibit fibrosis. These results suggest that SAP is a constitutive, and at high levels a dominant, regulatory signal in the innate immune system. SAP is a member of the pentraxin family that includes C-polysaccharide reactive protein (CRP) and pentraxin-3 (PTX3). Although CRP has strong sequence and structural similarity to SAP, CRP is a major marker of inflammation, but in some animal models CRP potentiates inflammation, and in other models CRP inhibits inflammation. In an effort to resolve this discrepancy, we found that CRP induces the differentiation of monocytes into Mreg, but induces macrophages to polarize into M1. To gain insight into a fundamental mechanism used to regulate the innate immune system, we propose three specific aims to elucidate the molecular mechanism used by pentraxins to regulate macrophage phenotype. Our first aim is to test the hypothesis that pentraxins can have different effects on macrophage differentiation compared to macrophage polarization, and test the hypothesis that ligands that bind pentraxins affect pentraxin signaling. Even though SAP, CRP, and PTX3 have distinct effects on macrophage phenotype, they all bind to Fc? receptors on cells. Our second aim is to distinguish between models where SAP activates some Fc? receptors and CRP (and/or PTX3) activates other Fc? receptors, and models where one or more of the pentraxins signals through other receptors to regulate macrophage phenotype. Our third aim is to determine the contribution of human Fc? receptors to pentraxin regulation of human macrophage phenotype. We will then use this information to screen for compounds that block the binding of a given pentraxin to a given Fc? receptor, and thus in the presence of the pentraxin, alter macrophage phenotype. Together, this work will help to elucidate a novel mechanism used by the innate immune system to regulate macrophage differentiation, and may lead to new therapies for macrophage-associated diseases.

描述(申请人提供)：巨噬细胞在结核病、利什曼病、慢性炎症、自身免疫性疾病、动脉粥样硬化、肥胖症、哮喘、纤维化和癌症等疾病中发挥重要作用，并且巨噬细胞是炎症性M1、促纤维化的M2a还是免疫调节性M2reg，其疾病进展受到强烈影响。单核细胞分化为M1、M2a或M2reg被认为是对炎症或修复过程中释放的信号的反应。出乎意料的是，一种名为血清淀粉样蛋白(SAP)的构成血浆蛋白会诱导单核细胞变成M2受体巨噬细胞。M2a巨噬细胞诱导和产生的信号与纤维化有关。在纤维化动物模型中注射SAP可以忽略这些信号，诱导M2reg分化，并抑制纤维化。这些结果表明，SAP是先天免疫系统中的一个结构性的，并且在高水平上是一个主导的调节信号。SAP是五肽家族的一员，包括C-多糖反应蛋白(CRP)和五肽-3(PTX3)。虽然CRP在序列和结构上与SAP有很强的相似性，但CRP是炎症的主要标志，但在一些动物模型中，CRP增强炎症，在另一些模型中，CRP抑制炎症。为了解决这一差异，我们发现，CRP诱导单核细胞分化为MRG，但诱导巨噬细胞分化为M1。为了深入了解调节先天性免疫系统的基本机制，我们提出了三个特定的目标，以阐明戊四氮调节巨噬细胞表型的分子机制。我们的第一个目标是检验五肽对巨噬细胞分化的影响不同于巨噬细胞极化的假说，并检验结合五肽的配体影响五肽信号的假说。尽管SAP、CRP和PTX3对巨噬细胞表型有不同的影响，但它们都与Fc？细胞上的受体。我们的第二个目标是区分SAP激活某些FC？受体和CRP(和/或PTX3)激活其他Fc？受体，以及一个或多个五肽通过其他受体发出信号来调节巨噬细胞表型的模型。我们的第三个目标是确定人类Fc？五肽受体对人巨噬细胞表型的调节。然后我们将使用这些信息来筛选阻止给定的五辛与给定的Fc结合的化合物？受体，从而在五肽存在的情况下，改变巨噬细胞的表型。总之，这项工作将有助于阐明先天免疫系统调节巨噬细胞分化的新机制，并可能为巨噬细胞相关疾病带来新的治疗方法。