STAT3 and its Acetylation in Acute Lung Injury

描述（由申请方提供）：急性肺损伤（ALI）及其进展为成人呼吸窘迫综合征（ARDS）仍然是危重患者发病率和死亡率的主要因素。虽然不断扩展的知识涉及的精氨酸转录因子网络提供了新的见解急性肺部炎症反应，阐明这些炎症相关的转录因子在肺部的功能仍然是一个艰巨的挑战。STAT3作为一种转录因子，参与许多细胞因子的信号传导途径，这些细胞因子受细胞因子信号传导抑制因子（SOCS）家族（包括SOCS 3）的调节。虽然STAT3在肺内的多种细胞类型中表达，但是关于STAT3的功能作用以及STAT3调节急性肺炎症反应的分子机制知之甚少。此外，对于STAT3在肺中的激活是如何调节的，还没有明确的理解。我们的初步数据表明，STAT3可以参与肺部炎症结果，似乎在IgG免疫复合物和LPS肺损伤模型和肺泡巨噬细胞中发挥双重作用。本研究的假设是，STAT3可能通过激活多个靶基因在ALI期间发挥其体内调节功能，然后差异调节Fc3R介导的和TLR4介导的肺中的炎症反应。因此，本研究旨在阐明STAT3和SOCS3信号在IgG免疫复合物或LPS肺内沉积后发生的ALI中的作用及其分子机制。在第一个目标中，我们将寻求初步的信息，即siRNA介导的STAT3在体内的抑制加重了ALI的IgG免疫复合物模型中的损伤，并减弱了ALI的LPS模型中的损伤，并确定促炎和抗炎介质的测量是否与ALI结果相关。在第二个目标中，我们将定义STAT3乙酰化和乙酰化调节肺泡巨噬细胞和肺损伤中STAT3活性的分子机制。在第三个目标中，我们将确定SOCS3调节IgG免疫复合物诱导和LPS诱导的肺泡巨噬细胞中STAT3活化和炎症反应的机制。将进行蛋白质组学分析以鉴定SOCS3相互作用蛋白。我们的研究结果有望提供有关肺部炎症级联反应以及STAT3和SOCS3在肺部炎症反应中的调节作用的重要信息。这些知识将代表一种新的范式，用于接近开发新的治疗靶点治疗ALI。项目叙述：本拟议项目将研究STAT3是否有助于免疫复合物和脓毒症相关的急性肺损伤。该项目还将确定是否翻译后机制，如蛋白质乙酰化和蛋白质-蛋白质相互作用有助于STAT3活性在急性肺损伤。这些研究对于确定治疗急性肺损伤的新靶点至关重要。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and its progression to adult respiratory distress syndrome (ARDS) remain leading factors of morbidity and mortality in critically ill patients. Although the expanding knowledge involving the cytokine-transcription factor network has provided new insights into the acute lung inflammatory responses, elucidation of the function of these inflammation-related transcription factors in the lung is still a daunting challenge. Functioning as a transcription factor, STAT3 participates in the signaling pathways for many cytokines that are regulated by the suppressor of cytokine signaling (SOCS) family, including SOCS3. While STAT3 is expressed in various cell types in lung, little is known about the function role of STAT3 and the molecular mechanism exerted by STAT3 to regulate acute lung inflammatory responses. Furthermore, there is no clear understanding of exactly how STAT3 activation is regulated in the lung. Our preliminary data indicate that STAT3 can participate in lung inflammatory outcomes and seems to play a dual role in both IgG immune complex and LPS lung injury models and alveolar macrophages. The hypothesis of this study is that STAT3 may exert its regulatory function in vivo during ALI by activating multiple target genes, which then differentially regulate Fc3R-mediated and TLR4-mediated inflammatory responses in the lung. Therefore, this study is designed to elucidate the roles of STAT3 and SOCS3 signaling in ALI occurring after intrapulmonary deposition of IgG immune complex or LPS, and the underlying molecular mechanisms. In the first aim, we will pursue preliminary information that siRNA-mediated suppression of STAT3 in vivo intensifies injury in IgG immune complex model of ALI and attenuates injury in the LPS model of ALI and determine if measurements of the pro- and anti-inflammatory mediators correlate with ALI outcomes. In the second aim, we will define STAT3 acetylation and molecular mechanisms by which acetylation regulates STAT3 activity in alveolar macrophages and lung injury. In the third aim, we will determine the mechanisms by which SOCS3 regulates IgG immune complex-induced and LPS-induced STAT3 activation and inflammatory response in alveolar macrophage. Proteomic analysis will be performed to identify SOCS3 interacting proteins. The results of our studies are expected to provide important information on inflammatory cascades in the lung and the regulatory roles of STAT3 and SOCS3 in the lung inflammatory response. This knowledge will represent a new paradigm for approaching the development of new therapeutic targets for treatment of ALI. PROJECT NARRATIVE: This proposed project will investigate whether STAT3 contributes to immune complex and sepsis-related acute lung injury. This project will also define if post-translational mechanisms such as protein acetylation and protein-protein interaction contribute to STAT3 activity in acute lung injury. These studies will be essential to identify novel therapeutic targets for treatment of acute lung injury.