Degradation of Toll-Like Receptor 8 by RNF216 in response to plasma MicroRNAâs â A Novel Mechanism Regulating Inflammation in Acute Lung Injury

RNF216 响应血浆 MicroRNA 降解 Toll 样受体 8 – 调节急性肺损伤炎症的新机制

• 批准号: 10539334
• 负责人: John W Evankovich
• 金额: $ 16.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539334
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Authorization documentation; Award; Bioinformatics; Biology; Cell physiology; Cellular biology; Cessation of life; Characteristics; Clinical; Critical Care; Cytoplasmic Tail; Data; Data Set; Degradation Pathway; Development; Doctor of Philosophy; Endosomes; Family; Gene Expression; Gene Proteins; Hypersensitivity; Infection; Inflammation; Inflammatory; Inflammatory Response; International; Invaded; K-Series Research Career Programs; Ligands; Lung; Lysine; Mediating; Medicine; Mentors; MicroRNAs; Modeling; Molecular; Molecular Profiling; Natural Immunity; Organ failure; Pathologic; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Phenotype; Physicians; Plasma; Post-Translational Protein Processing; Process; Proteins; RNA; Research; Research Methodology; Research Personnel; Respiratory Failure; Scientist; Signal Pathway; Signal Transduction; Site; Source; Survivors; System; TLR8 gene; Training; Translational Research; Ubiquitin; Ubiquitination; Universities; Work; authority; career; cohort; cytokine; immune activation; immunogenic; inflammatory modulation; insight; lung injury; mRNA Expression; member; molecular modeling; monocyte; mortality; multicatalytic endopeptidase complex; novel; novel strategies; pathogen; programs; protein degradation; protein expression; recruit; response; skills; translational scientist; ubiquitin-protein ligase

This application is for a K08 Mentored Clinical Scientist Research Career Development Award entitled “Degradation of Toll-Like Receptor 8 by RNF216 in response to plasma MicroRNA’s – A Novel Mechanism Regulating Inflammation in Acute Lung Injury”. I am a physician in pulmonary and critical care medicine at the University of Pittsburgh. I am applying for this award to acquire advanced training in cell biology, translational research methods, and bioinformatics to develop my career as a physician scientist focused on the study of acute respiratory distress syndrome (ARDS). The main objective of my proposal is to determine how a novel Toll-Like Receptor 8 (TLR8) degradation pathway in monocytes regulates severe lung injury. TLR8 is a pattern recognition receptor that senses immunogenic RNA, including some host-derived plasma microRNA’s. TLR8 activation initiates signaling leading to the secretion of cytokines, contributing to excessive inflammation that is characteristic of severe ARDS. My preliminary data indicate that TLR8 is degraded in monocytes in a mechanism dependent on the post-translational modification of ubiquitination. Further, I have identified a candidate ubiquitin- transferring E3 ligase termed RNF216 responsible for targeting TLR8 for degradation, and I observe that RNF216 mRNA expression is decreased in patients with ARDS. Lastly, I have identified a subset of circulating plasma microRNA’s in ARDS subjects that may function as novel TLR8 ligands. The aims of this study are: i) to define the mechanism regulating TLR8 protein levels by the ubiquitin/proteasome system in monocytes ii) to determine if RNF216 modulates inflammatory signaling by directing TLR8 degradation and define RNF216 expression in ARDS, and iii) to examine plasma miRNA’s in ARDS subjects as TLR8 ligands. These studies will provide insight into a novel pathobiologic model whereby TLR8 degradation, regulated by RNF216 mediated protein ubiquitination, controls inflammation in response to host-derived plasma microRNA’s in ARDS. Plasma miRNA-induced TLR8 activation, augmented by reduced RNF216 mediated ubiquitination and degradation of TLR8, may drive excessive inflammation. Thus, modulating TLR8 degradation may be a novel strategy to reduce excessive inflammatory responses in ARDS. This project will provide me advanced skills in cell biology and bioinformatic approaches to analyze molecular datasets. I will be trained in translational research methodologies to strengthen my development into an independent investigator. I have committed mentoring from our Division Chief, Dr. Rama Mallampalli and a PhD comentor in Dr. Bill Chen. Additionally, my mentoring committee includes Dr. Robert Lafyatis – an international expert in innate immunity, Dr. Stephen Chan – an authority in translational miRNA biology, and Dr. Bryan McVerry – a superb translational scientist and member of the Acute Lung Injury Center of Excellence overseeing the clinical Acute Lung Injury program. My work will be completed within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which is committed to the development of physician scientists.

此申请是为了获得K08指导临床科学家研究职业发展奖