Extracellular RNA amplifies lung inflammation

细胞外RNA放大肺部炎症

• 批准号: 8994177
• 负责人: Michael Paul Mohning
• 金额: $ 4.16万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994177
• 关键词: Acids; Acute; Acute Lung Injury; Adaptor Signaling Protein; Adoptive Transfer; Alveolar Macrophages; Alveolus; Animals; Antiviral Agents; Apoptosis; Apoptotic; Attenuated; Biology; Cells; Colorado; Critical Care; Cytoplasmic Receptors; Development; Disease; Endosomes; Extracellular Space; Faculty; Fellowship; Fellowship Program; Future; Goals; Health; Host Defense Mechanism; Inflammation; Inflammatory; Inflammatory Response; Injury; Internal Medicine; Knowledge; Lead; Liquid substance; Lung; Lung Inflammation; Lung diseases; Medicine; Mentors; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Necrosis; Pathway interactions; Pattern; Play; Principal Investigator; Property; Pulmonology; RNA; Research; Research Personnel; Residencies; Resolution; Ribonucleases; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; TLR3 gene; TLR7 gene; Testing; Therapeutic Studies; Toll-like receptors; Training; Training Programs; Universities; Virus; Virus Diseases; Work; base; career; cytokine; extracellular; follower of religion Jewish; injured; insight; lung injury; lung repair; macrophage; member; mouse model; novel; novel therapeutic intervention; pathogen; receptor; research study; response; sensor

 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.

 描述（由适用提供）：该提案描述了一项为期两年的研究奖学金计划，该计划将使主要研究人员开始发展肺医学的学术生涯。首席研究人员已经完成了一项彻底的内科居住培训计划，目前正在作为肺和重症监护医学研究员进行培训。拟议的研究将研究细胞外核酸在肺部炎症环境中的作用，这应该被证明适用于许多炎症性肺部条件。巨噬细胞生物学专家威廉·詹森（William Janssen）博士将在他在肺部感染领域的科学发展过程中成为主要研究人员的两个联合主管之一。 Janssen博士是丹佛国家犹太人卫生部肺重症监护医学部以及科罗拉多州丹佛大学的良好尊敬的教职员工。彼得·亨森（Peter Henson）博士还将担任联合学，他是肺部犹太人和加州大学丹佛分校的肺部受伤和维修领域的专家。亨森博士在为独立调查员带来心理化研究员方面非常成功。我们的总体研究目标是确定细胞外核糖核酸（RNA）在促进肺部感染中的作用。我们假设这种细胞外RNA在肺损伤的情况下从坏死和凋亡细胞中释放出来，是一种通过扩增感染的机制。我们将表征RNA，该RNA呈现在受伤和发炎的肺肺泡中，并阐明其发挥促炎作用的机制。在病毒感染的情况下，对细胞的RNA敏感性进行了最广泛的研究。从这些研究中，我们知道TLRS 3、7和8以及各种类似的RIG-I受体（RLR）可以响应RNA产生促炎性信号传导。我们的实验将使用LPS和酸诱导的急性肺损伤的小鼠模型来研究RNA的促炎特性。我们将使用传感器缺陷的小鼠菌株研究在我们的肺损伤模型中TLR3，TLR7和线粒体抗病毒信号传导蛋白（MAV）（MAVS），这是常见的RLR适配器蛋白。我们还将研究细胞外RNA的酶促降解是否会衰减炎症反应。确定细胞外RNA如何放大炎症反应将为炎症和损伤中的肺部生物学提供新的见解。这可能适用于各种炎症性肺部疾病，并可能在将来展示新的治疗干预措施的机会。当首席研究者从奖学金转移到初级研究员到独立研究人员时，它还将为Futre工作提供基础。