Matrix Metalloproteinase Driven Lung Inflammation in RSV disease

RSV 疾病中基质金属蛋白酶驱动的肺部炎症

• 批准号: 9273626
• 负责人: Michele Kong
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273626
• 关键词: Advisory Committees; Alabama; Antiviral Agents; Area; Award; Biological Markers; Biology; Bronchiolitis; Cells; Chemotactic Factors; Child; Childhood; Chimeric Proteins; Clinical; Clinical Sciences; Clinical Trials; Collagen; Communicable Diseases; Coupled; Data; Development; Disease Management; Doctor of Medicine; Doctor of Philosophy; Environment; Epithelial; Epithelial Cells; Event; Failure; Funding; Gelatinase B; Generations; Genetic Transcription; Glycine; Goals; Hospitalization; Host Defense; Human; Immunology; In Vitro; Infant; Infection; Inflammation; Inflammatory; Injury; K-Series Research Career Programs; Knockout Mice; Laboratories; Leukocyte Elastase; Lung; Lung Inflammation; Lung diseases; Macrolides; Master' s Degree; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediator of activation protein; Mentors; Molecular; Morbidity - disease rate; Mus; Outcome; Outcome Measure; Pathogenesis; Pathway interactions; Peer Review; Peptide Hydrolases; Physicians; Production; Proline; Protease Inhibitor; Proteolysis; Publications; Pulmonary Inflammation; Pulmonary Pathology; Research; Research Activity; Research Personnel; Resource Development; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory physiology; Respiratory syncytial virus; Risk; Sampling; Science; Scientist; Severity of illness; Signal Transduction; Small Interfering RNA; Specificity; Stimulus; System; Techniques; Testing; Tissue Inhibitor of Metalloproteinase-1; Training; Training Programs; Translational Research; Translations; Universities; Ventilator; Viral; Viral Load result; Viral load measurement; Virus Diseases; Virus Replication; advanced disease; airway epithelium; airway inflammation; base; career; career development; clinical predictors; clinically relevant; cytokine; disorder control; endotracheal; improved; in vivo; infancy; inhibitor/antagonist; lung injury; meetings; mortality; mouse model; neutrophil; new therapeutic target; novel; novel therapeutics; pancreatic elastase II; pathogen; pediatric patients; programs; prospective; public health relevance; research facility; small molecule; small molecule inhibitor

DESCRIPTION (provided by applicant): This proposal describes a 5-year mentored training program to provide the candidate, Dr. Michele Kong, with intensive training in the areas of cellular and molecular mechanisms of inflammation, matrix destruction, protease antiprotease imbalance and pathogenesis of RSV-induced respiratory failure, which will facilitate her development as an independent investigator. Dr. Kong has a long track record of academic excellence and commitment to a research career. In her career development and research activities, Dr. Kong will be mentored by J. Edwin Blalock, Ph.D. and Amit Gaggar, M.D., who are recognized leaders in immunology, inflammation and protease biology. Dr. Kong has also assembled an advisory committee with expertise in the fields of inflammation, infectious disease and translational research (Drs. Rich Whitley, Namasivayam Ambalavanan, Eric Sorscher and JP Clancy), all of whom have given Dr. Kong their commitment to the successful completion of the proposed research aims, and in assisting her transition to being an independent physician-scientist. The University of Alabama at Birmingham (UAB) provides the ideal environment for training physician-scientists by combining state of the art research facilities, excellent career development resources and a broad clinical base. The fundamental hypotheses of this proposal are: 1) RSV is a potent stimulus of MMP-9 release from primary human airway epithelial cells, and that MMP-9 facilitates RSV propagation in airway epithelia through fusion protein proteolysis; 2) MMP-9 facilitates RSV infection and is a modulator of early viral-induced lung inflammation and injury; 3) MMP-9 activity is dysregulated in pediatric patients with RSV-induced respiratory failure, directly correlating with the generation of downstream chemotactic PGP fragments and clinical indicators of disease severity. The candidate's short-term goals during the period of this career development award is to complete the aims of this research plan, obtain a Master's degree in Biomedical Science in Clinical and Translational Science at UAB, present annually at scientific meetings and submit five or more peer- reviewed publications. In the latter half of the award period, she will submit an application for independen R01 funding. Her long-term goals are to develop an independent research program with the ultimate goal of identifying new biomarkers and creating novel therapies for RSV disease, based on an improved understanding of matrix destruction, airway and lung inflammation, with an emphasis host defense and host- pathogen interaction.

描述（由申请人提供）：本提案描述了一项为期5年的指导培训计划，旨在为候选人Michele Kong博士提供炎症细胞和分子机制、基质破坏、蛋白酶抗蛋白酶失衡和RSV诱导的呼吸衰竭发病机制等领域的强化培训，这将有助于其成为独立研究者。江博士拥有长期的学术卓越记录和对研究事业的承诺。在她的职业发展和研究活动中，孔博士将由J. Edwin Blalock博士指导。和Amit Gaggar医学博士他们是免疫学、炎症和蛋白酶生物学领域公认的领导者。Kong博士还组建了一个具有炎症，传染病和转化研究领域专业知识的咨询委员会（Rich Whitley博士，Namasivayam Ambalavanan博士，Eric Sorscher博士和JP Clancy博士），他们都致力于成功完成拟议的研究目标，并协助她过渡到独立的医生科学家。亚拉巴马大学伯明翰分校（UAB）通过结合最先进的研究设施，优秀的职业发展资源和广泛的临床基础，为培养医生科学家提供了理想的环境。该建议的基本假设是：1）RSV是从原代人气道上皮细胞释放MMP-9的有效刺激物，并且MMP-9通过融合蛋白质水解促进RSV在气道上皮中的增殖; 2）MMP-9促进RSV感染并且是早期病毒诱导的肺部炎症和损伤的调节剂; 3）MMP-9活性在患有RSV诱导的呼吸衰竭的儿科患者中失调，与下游趋化性PGP片段的产生和疾病严重程度的临床指标直接相关。候选人在此职业发展奖期间的短期目标是完成本研究计划的目标，获得UAB临床和转化科学生物医学科学硕士学位，每年出席科学会议并提交五份或更多同行评审的出版物。在奖励期的后半段，她将提交独立R 01资助申请。她的长期目标是开发一个独立的研究计划，其最终目标是确定新的生物标志物并为RSV疾病创造新的疗法，基于对基质破坏，气道和肺部炎症的更好理解，重点是宿主防御和宿主-病原体相互作用。