Regulation of Lung Authopagy and Inflammation

肺自体解剖和炎症的调节

基本信息

批准号：
9026495
负责人：
ARSHAD RAHMAN
金额：
$ 38.38万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2013-08-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026495
关键词：
3-methyladenine Acute Lung Injury Address Adult Respiratory Distress Syndrome Apoptosis Attenuated Autophagocytosis Biochemical Blood Vessels Breathing Chloroquine Complementary DNA Data Development Disease Dose Down-Regulation Endothelial Cells Endothelium Event FRAP1 gene Gene Delivery Heart In Vitro Infiltration Inflammation Inflammatory Injury Knockout Mice Lead Link Lipopolysaccharides Lung Lung Inflammation Mediating Mediator of activation protein Molecular Molecular and Cellular Biology Monitor Mus Pathogenesis Physiology Preventive Process Protein Isoforms Publishing Regulation Role Signal Pathway Signal Transduction Site Testing Therapeutic Thrombin Time Work aerosolized base genetic approach in vivo inhibition of autophagy inhibitor/antagonist insight interdisciplinary approach loss of function lung injury mouse model novel novel therapeutic intervention novel therapeutics phospholipase C epsilon public health relevance reconstitution research study

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this application is to understand how autophagy and inflammation, particularly in the context of lung endothelium, are activated in association to control acute lung injury (ALI). The rationale for the study is based on our novel finding that phospholipase C epsilon (PLCε), a bifunctional PLC isoform with primary sites of expression in the lung and heart, acts as a critical regulator of autophagy and inflammation in the lung and that inhibiting autophagy ameliorates LPS-induced lung vascular leak. Our published data and ongoing work show that mechanistic (formerly mammalian) target of rapamycin (MTOR), a known inhibitor of autophagy, also functions as endogenous modulator of EC inflammation. Furthermore, we have identified an important role of PLCε in causing down-regulation of MTOR levels in the lungs of mice challenged with LPS. Based on these findings, we propose to test the hypothesis that activation of endothelial PLCε down-regulates MTOR levels/signaling to induce autophagy in association with inflammation to cause ALI. Aim 1 will (i) ascertain the role of PLCε in mediating EC autophagy and inflammation, (ii) assess the contribution of autophagy to EC inflammation and apoptosis, (iii) determine the in vivo role of endothelial PLCε in causing lung inflammation and injury, and (iv) address the in vivo role of endothelial PLCε in causing lung autophagy and evaluate the contribution of this event in the mechanism of lung inflammation and injury. Aim 2 will (i) determine the role of PLCε in suppressing MTOR levels/signaling to cause EC autophagy and inflammation, (ii) determine the in vivo relevance of suppression of endothelial MTOR levels/signaling in causing lung vascular autophagy and inflammatory injury, and (iii) evaluate the therapeutic potential of autophagy inhibition against evolving ALI. These studies will utilize multidisciplinary approaches ranging from biochemical, cellular, and molecular biology to in vivo gene delivery and lung physiology, and take advantage of conditional PLCε and MTOR knockout mice. The creative integration of in vitro and in vivo studies will provide novel insights into the integrated regulation of EC autophagy and inflammation in ALI and may lead to novel therapeutic interventions to control ALI/ARDS.

描述（由申请人提供）：本申请的总体目标是了解自噬和炎症（特别是在肺内皮的情况下）如何被激活以控制急性肺损伤（ALI）。该研究的基本原理是基于的。我们的新发现是磷脂酶 C epsilon (PLCε) 是一种双功能 PLC 亚型，主要表达位点在肺和心脏，它是肺自噬和炎症的关键调节因子，并且抑制自噬可改善 LPS 诱导的肺血管渗漏。我们已发表的数据和正在进行的工作表明，雷帕霉素的机械靶标 (MTOR)（一种已知的自噬抑制剂）也可作为 EC 炎症的内源性调节剂。 PLCε 在引起 LPS 攻击的小鼠肺部 MTOR 水平下调中的重要作用基于这些发现，我们建议检验内皮细胞激活的假设。 PLCε 下调 MTOR 水平/信号传导以诱导与炎症相关的自噬，从而导致 ALI。目标 1 将 (i) 确定 PLCε 在介导 EC 自噬和炎症中的作用，(ii) 评估自噬对 EC 炎症和细胞凋亡的贡献。，（iii）确定内皮 PLCε 在引起肺部炎症和损伤中的体内作用，以及（iv）解决内皮 PLCε 在引起肺部炎症和损伤中的体内作用目标 2 将 (i) 确定 PLCε 在抑制 MTOR 水平/信号传导以引起 EC 自噬和炎症中的作用，(ii) 确定自噬的体内相关性。抑制内皮 MTOR 水平/信号传导导致肺血管自噬和炎症损伤，以及 (iii) 评估自噬抑制对演进性 ALI 的治疗潜力。生物化学、细胞和分子生物学到体内基因传递和肺生理学，并利用条件性 PLCε 和 MTOR 敲除小鼠的体外和体内研究的创造性整合将为 EC 自噬和炎症的综合调节提供新的见解。 ALI 并可能导致控制 ALI/ARDS 的新治疗干预措施。