Regulation of Lung Authopagy and Inflammation

肺自体解剖和炎症的调节

• 批准号: 8576134
• 负责人: ARSHAD RAHMAN
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8576134
• 关键词: 3-methyladenine; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Apoptosis; Ascaridil; Attenuated; Autophagocytosis; Biochemical; Blood Vessels; Breathing; Chloroquine; Complementary DNA; Data; Development; Disease; Dose; Down-Regulation; Endothelial Cells; Endothelium; Event; Gene Delivery; Genetic; Heart; In Vitro; 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; Sirolimus; Site; Testing; Therapeutic; Thrombin; Time; Work; aerosolized; base; 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

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 (PLC¿), 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 PLC¿ 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 PLC¿ down-regulates MTOR levels/signaling to induce autophagy in association with inflammation to cause ALI. Aim 1 will (i) ascertain the role of PLC¿ 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 PLC¿ in causing lung inflammation and injury, and (iv) address the in vivo role of endothelial PLC¿ 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 PLC¿ 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 PLC¿ 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（由应用程序提供）：本应用的总体目的是了解自噬和感染，尤其是在肺部内皮的背景下如何激活以控制急性肺损伤（ALI）。该研究的基本原理是基于我们的新颖发现，即磷脂酶C epsilon（PLCCO）是一种双功能PLC同工型，具有肺和心脏中主要表达位点，是肺中自噬和炎症的关键调节剂，并且可以抑制自噬lps lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung。我们已发表的数据和正在进行的工作表明，已知的自噬抑制剂的雷帕霉素（MTOR）的机械（以前是哺乳动物）的靶标也是EC炎症的内源性调节剂。此外，我们已经确定了PLC知识在引起MTOR水平下调的重要作用。基于这些发现，我们建议检验以下假设：内皮PLCC的激活下调MTOR水平/信号传导以诱导与炎症相关的自噬以引起ALI。目标1将（i）确定PLCC在介导EC自噬和注射中的作用，（ii）评估自噬对EC注射和凋亡的贡献，（iii）确定内皮PLC的体内作用在导致肺部感染和（IV）贡献的贡献和（iv）贡献中的贡献中，并在造成肺部的贡献中，并促进了促成型的促进，并在造成肺部的作用中，在造成肺部的作用中，在造成肺部感染中，在造成肺部的促进症中，在造成肺部感染中，在造成肺部感染中，在造成肺部感染和造成了造成肺部的作用，在造成肺部感染和造成了造成肺部的作用，从而在肺部感染中造成了造成的作用。肺部注射和损伤的机制。目标2（i）将确定PLC在抑制MTOR水平/信号传导中引起EC自噬和注射的作用；这些研究将利用从生化，细胞和分子生物学到体内基因递送和肺部生理学的多学科方法，并利用有条件的PLC和MTOR敲除小鼠。体外和体内研究的创造性整合将为ALI的EC自噬和注射的综合调节提供新的见解，并可能导致用于控制ALI/ARDS的新型治疗干预措施。