ROLE OF THE AHR IN REGULATING INFLAMMASOME ACTIVATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这个Cobre子项目的目标是详细分析芳烃受体(AhR)通过与Nlrp3炎症体成分的相互作用在调节肺部炎症反应中的作用。这项拟议的研究将显著提高我们对慢性炎症性疾病的理解，并将在人类疾病动物模型的背景下产生关于AhR如何调节肺部炎症的独特和高影响力的信息。这也将促进我们对AhR在肺功能和肺免疫中的作用的基本理解。在第一个目标中，我们将确定AhR在体外和体内对有害颗粒反应的炎症信号调节中的作用。在第二个目标中，我们将利用TCDD和AhR的其他各种配体，证明AhR的激活调节炎症信号。在第三个具体目标中，我们将确定调控炎症环境产生的炎性小体-AhR界面的性质和分子组成。本研究涉及一种新的炎症体信号调控系统，在该系统中，AhR负性调节有害颗粒诱导的炎症反应。对通过AhR激活抑制炎症体激活和慢性炎症的机制的更好的了解将为治疗的发展提供理论靶点。此外，这一应用具有创新性，因为预计它将有助于开发新的治疗目标，以管理呼吸道疾病，包括颗粒引起的炎症和纤维化，这将对人类健康产生重大的积极影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this COBRE subproject is to provide a detailed analysis of the role of the aryl hydrocarbon receptor (AhR) in regulating pulmonary inflammation in response to harmful particulates through its interactions with components of the Nlrp3 inflammasome. The proposed research will significantly improve our understanding of chronic inflammatory disorders and will generate unique and high impact information regarding how the AhR regulates pulmonary inflammation in the context of animal models of human disease. It will also advance our basic understanding of the role of the AhR in lung function and pulmonary immunity. In the first aim, we will define the role of the AhR in the regulation of inflammatory signaling both in vitro and in vivo in response to harmful particulates. In the second aim, using TCDD and various other ligands of the AhR, we will demonstrate that AhR activation regulates inflammatory signaling. In the third specific aim, we will identify the nature and molecular components of the inflammasome-AhR interface that regulate the generation of an inflammatory environment. This study deals with a novel regulatory system for inflammasome signaling in which the AhR negatively regulates the inflammatory responses induced by harmful particulates. Improved knowledge regarding mechanisms for suppressing inflammasome activation and chronic inflammation via AhR activation will provide rationale targets for development of therapeutics. Furthermore, this application is innovative in that it is expected to contribute to the development of novel therapeutic targets for the management of respiratory illnesses, including particulate-induced inflammation and fibrosis, which would have a significant, positive effect on human health.