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Regulation of cytosolic pattern recognition receptor signaling in macrophages

巨噬细胞胞质模式识别受体信号传导的调节

基本信息

批准号：
10356799
负责人：
Christian Stehlik
金额：
$ 54.26万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-11 至 2024-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356799
关键词：
Ablation Acute Address Affect Alzheimer&apos s Disease Arthritis Asbestosis Asthma Atherosclerosis Biochemical CASP1 gene Cell Death Chronic Clinical Complex Data Diabetes Mellitus Disease Family Funding Genes Genetic Genetic Transcription Genetic study Goals Gouty Arthritis Health Homeostasis Host Defense Human Immune Immune response Immune signaling Impairment Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferon Type I Interferon-beta Interferons Interleukin-1 beta Interleukin-18 Interleukins Link Malignant Neoplasms Mediating Modeling Molecular Molecular Genetics Multiple Sclerosis Mus NF-kappa B Pathology Pathway interactions Patients Pattern recognition receptor Phosphorylation Production Protein Family Proteins Psoriasis Publications Receptor Signaling Regulation Reporting Research Resolution Rheumatoid Arthritis Role Signal Pathway Signal Transduction Silicosis Tissues Transcriptional Activation Transgenic Mice autoinflammatory base cytokine design improved in vivo inhibitor insight kidney dysfunction macrophage marenostrin member mouse model mutant novel novel therapeutics pathogen prevent response sensor tool wound healing

项目摘要

Acute inflammatory responses are highly beneficial for host defense to eliminate infections and to initiate wound healing. However, inappropriate, uncontrolled inflammatory responses cause the detrimental pathologies of an expanding spectrum of inflammatory diseases. A key pathway promoting inflammatory responses is the inflammasome, which is a signaling platform composed of an upstream sensor of the NLR or ALR families, the adaptor ASC and Caspase-1. Inflammasome activation promotes activation of Caspase-1 and subsequent release of interleukin (IL)-1b and IL-18 and the induction of pyroptotic cell death. Inflammasomes are activated by a 2-step mechanism involving priming and activation, but the precise regulatory mechanisms that control and maintain a balanced inflammasome response and consequently homeostasis, are still poorly understood, but are key for developing novel and improved therapies. The research outlined in this renewal application is focused on elucidating the molecular mechanism by which two by us discovered inhibitors of this response function to dampen inflammation, and how this activity is important to prevent inflammatory disease. We discovered all three members of the PYRIN domain (PYD)- only protein (POP) family of small endogenous proteins, which we demonstrated to function by inhibiting and resolving inflammatory responses. POPs very recently evolved in humans, but are lacking from mice and we generated novel transgenic mouse models to study POPs in macrophages in vivo. During the 1st funding period, we discovered the precise mechanism by which each of these POPs inhibit inflammasome activation at the level of inflammasome assembly. We also discovered that two members have a second unique inflammasome-independent role in regulating priming of macrophages, which is also the first key step in inflammasome activation. Our main goal for this renewal application is to delineate the precise mechanisms by which POP2 and POP3 regulate inflammatory priming of macrophages, employing biochemical, molecular and genetic studies, focusing on type I interferon (IFN-I) production and non-canonical NF-kB activation. Hence, POPs regulate inflammatory responses of macrophages at several levels, which ultimately prevents cytokine release. Therefore, dissecting these unique POP2 and POP3 activities will provide novel insights into how this important, but still poorly understood protein family regulates key innate immune signaling pathways, which is therefore highly significant for better understanding inflammatory disease pathologies. Collectively, our results will therefore have tremendous implications for human health.

急性炎症反应对于宿主防御消除感染和启动防御非常有益。伤口愈合。然而，不适当的、不受控制的炎症反应会导致有害的扩大范围的炎症性疾病的病理学。促进炎症的关键途径反应是炎症小体，它是由 NLR 的上游传感器或 ALR 家族、适配器 ASC 和 Caspase-1。炎症小体激活促进 Caspase-1 激活随后释放白细胞介素 (IL)-1b 和 IL-18，并诱导焦亡细胞死亡。炎症小体通过涉及启动和激活的两步机制被激活，但精确的控制和维持平衡的炎症反应的调节机制，从而体内平衡仍然知之甚少，但却是开发新的和改进的疗法的关键。本次更新申请中概述的研究重点是阐明分子机制我们的两个人发现了这种反应的抑制剂可以抑制炎症，以及这种活性是如何发挥作用的对于预防炎症性疾病很重要。我们发现了 PYRIN 结构域 (PYD) 的所有三个成员 - 唯一的蛋白质（POP）家族的小内源性蛋白质，我们证明其通过抑制和解决炎症反应。持久性有机污染物最近在人类中进化出来，但小鼠中却缺乏，我们建立了新的转基因小鼠模型来研究体内巨噬细胞中的持久性有机污染物。第一次融资期间在此期间，我们发现了每种 POP 抑制炎症小体激活的精确机制炎症小体组装水平。我们还发现两名成员有第二个独特的调节巨噬细胞启动的独立于炎症小体的作用，这也是巨噬细胞启动的第一个关键步骤炎症小体激活。我们此更新应用程序的主要目标是通过以下方式描述精确的机制：其中 POP2 和 POP3 通过生物化学、分子和分子机制调节巨噬细胞的炎症启动。遗传学研究，重点关注 I 型干扰素 (IFN-I) 的产生和非典型 NF-kB 激活。因此，POPs 在多个层面调节巨噬细胞的炎症反应，最终阻止细胞因子释放。因此，剖析这些独特的 POP2 和 POP3 活动将为我们提供新的见解这个重要但仍知之甚少的蛋白质家族如何调节关键的先天免疫信号通路，因此，这对于更好地了解炎症性疾病病理学具有非常重要的意义。总的来说，因此，我们的研究结果将对人类健康产生巨大影响。