Extracellular RNA amplifies lung inflammation

 描述(由申请人提供)：本提案描述了一项为期两年的研究奖学金计划，该计划将允许首席研究人员开始在肺部医学领域发展学术生涯。首席调查员已经完成了内科的全面住院医师培训计划，目前正在接受肺部和重症监护医学研究员的培训。这项拟议的研究将调查细胞外核糖核酸在肺部炎症环境中的作用，这应该被证明适用于一系列炎症性肺部疾病。巨噬细胞生物学专家威廉·詹森博士将成为首席研究员在肺部炎症领域的科学发展过程中的两名共同导师之一。詹森博士是丹佛国家犹太人健康中心和科罗拉多大学丹佛分校肺部重症监护医学部备受尊敬的教员。彼得·亨森博士也将担任共同导师，他是国家犹太人和加州大学丹佛分校的肺损伤和修复领域的专家。在指导研究员成为独立调查人员方面，汉森博士极为成功。我们的总体研究目标是确定细胞外核糖核酸(RNA)在促进肺部炎症中的作用。我们推测，在肺损伤的背景下，这种从坏死和凋亡细胞中释放出来的细胞外RNA是放大炎症的机制。我们将对存在于肺损伤和炎症的肺泡中的RNA进行表征，并阐明其发挥促炎作用的机制。在病毒感染的背景下，细胞对RNA的感知被研究得最广泛。从这些研究中，我们知道TLR3、7和8以及各种RIG-I样受体(RLR)可以产生促炎信号来响应RNA。我们的实验将使用小鼠的急性肺损伤模型，包括内毒素和酸诱导的，以研究RNA的促炎特性。我们将使用传感器缺陷小鼠品系来研究TLR3、TLR7和线粒体抗病毒信号蛋白(MAVS)在我们的肺损伤模型中的功能。我们还将研究细胞外RNA的酶降解是否会减弱炎症反应。确定细胞外RNA如何放大炎症反应将为炎症和损伤中的肺生物学提供新的见解。这可能适用于各种炎症性肺部疾病，并可能展示未来新的治疗干预措施的机会。它还将为未来的工作提供基础，因为首席调查员将从研究员职位晋升到初级研究员，再到独立研究员。

 DESCRIPTION (provided by applicant): This proposal describes a 2-year research fellowship program, which will allow the principal investigator to begin to develop an academic career in Pulmonary Medicine. The principal investigator has completed a thorough residency training program in Internal Medicine and is currently training as a fellow in Pulmonary and Critical Care Medicine. The proposed research will investigate the role of extracellular ribonucleic acids in the setting of inflammation in the lungs, which should prove to be applicable in a host of inflammatory lung conditions. Dr. William Janssen, an expert in macrophage biology will be one of two co-mentors to the principal investigator during in his scientific development in the field o lung inflammation. Dr. Janssen is a well-respected faculty member in the Pulmonary Critical Care Medicine Division at National Jewish Health in Denver, as well as at the University of Colorado Denver. Also serving as Co-Mentor will be Dr. Peter Henson, an expert in the field of lung injury and repair at National Jewish and UC Denver. Dr. Henson has been extremely successful in mentoring fellows into independent investigators. Our overall research goal is to determine the role of extracellular ribonucleic acids (RNA) in the promotion of lung inflammation. We hypothesize that this extracellular RNA, released from necrotic and apoptotic cells in the setting of lung injury serve as a mechanism by which inflammation is amplified. We will characterize the RNA, which is present in the alveoli of injured and inflamed lungs, and elucidate the mechanism by which it exerts its pro-inflammatory effect. The sensing of RNA by cells has been studied most extensively in the setting of viral infection. From those studies, we know that TLRs 3, 7, and 8 as well as the various RIG-I like receptors (RLR) can produce pro-inflammatory signaling in response to RNA. Our experiments will use mouse models of acute lung injury, both LPS and acid induced, to study RNA's pro- inflammatory properties. We will use sensor deficient mouse strains to study the function of TLR3, TLR7 and mitochondrial antiviral signaling protein (MAVS), which is the common RLR adaptor protein, in our lung injury models. We will also investigate whether the enzymatic degradation of the extracellular RNA will attenuate the inflammatory response. Determining how extracellular RNA can amplify the inflammatory response will provide novel insight into lung biology in inflammation and injury. This may be applicable to a variety of inflammatory lung conditions, and possibly demonstrate opportunities for new therapeutic interventions in the future. It will also provide a basis for futre work as the principal investigator moves from fellowship, to junior investigator, to independent researcher.