Extracellular RNA amplifies lung inflammation

 描述（由申请人提供）：本提案描述了一个为期2年的研究奖学金计划，该计划将允许主要研究者开始在肺部医学领域发展学术生涯。主要研究者已经完成了全面的内科住院医师培训计划，目前正在接受肺部和重症监护医学研究员的培训。 拟议的研究将调查细胞外核糖核酸在肺部炎症中的作用，这应该证明适用于许多炎症性肺部疾病。巨噬细胞生物学专家William Janssen博士将是主要研究者在肺部炎症领域科学发展期间的两名共同导师之一。Janssen博士是丹佛国家犹太健康中心肺部重症监护医学部以及科罗拉多丹佛大学备受尊敬的教员。彼得·亨森博士也将担任共同导师，他是国家犹太大学和丹佛加州大学肺损伤和修复领域的专家。汉森博士在指导研究员成为独立调查员方面非常成功。 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。我们假设，这种细胞外RNA，从坏死和凋亡细胞在肺损伤的设置释放作为一种机制，炎症被放大。我们将描述RNA的特征，RNA存在于受伤和发炎的肺的肺泡中，并阐明其发挥促炎作用的机制。在病毒感染的情况下，细胞对RNA的感知已经被最广泛地研究。从这些研究中，我们知道TLR 3、7和8以及各种RIG-I样受体（RLR）可以响应RNA产生促炎信号。我们的实验将使用LPS和酸诱导的急性肺损伤小鼠模型来研究RNA的促炎特性。我们将使用传感器缺陷小鼠品系来研究TLR 3、TLR 7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，MAVS是常见的RLR衔接蛋白。我们还将研究细胞外RNA的酶促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，并可能在未来展示新的治疗干预的机会。它还将为今后的工作奠定基础，因为主要研究员将从研究员变为初级研究员，再变为独立研究员。

 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.