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: 8842701
• 负责人: Michele Kong
• 金额: $ 11.83万
• 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/8842701
• 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; Health; Host Defense; Human; Immunology; In Vitro; Infant; Infection; Inflammation; Inflammatory; 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; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Outcome Measure; Pathogenesis; Pathology; Pathway interactions; Peer Review; Peptide Hydrolases; Peroxidases; Physicians; Pneumonia; Production; Proline; Protease Inhibitor; Proteins; Proteolysis; Publications; Pulmonary Inflammation; Research; Research Activity; Research Personnel; Resources; 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; 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; body system; career; career development; clinically relevant; cytokine; disorder control; endotracheal; improved; in vivo; infancy; inhibitor/antagonist; injured airway; long term hospitalization; lung injury; meetings; mortality; neutrophil; new therapeutic target; novel; pathogen; pediatric patients; programs; research and development; research facility; small molecule

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）：本提案描述了一个为期 5 年的指导培训计划，为候选人 Michele Kong 博士提供炎症、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，这将有助于她成为一名独立研究者。孔博士有着长期的卓越学术记录和对研究事业的奉献精神。在她的职业发展和研究活动中，Kong 博士将得到 J. Edwin Blalock 博士的指导。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 博士还组建了一个在炎症、传染病和转化研究领域拥有专业知识的咨询委员会（Rich Whitley 博士、Namasivayam Ambalavanan、Eric Sorscher 和 JP Clancy），所有这些人都向 Kong 博士承诺成功完成拟议的研究目标，并协助她过渡为一名独立的医师科学家。阿拉巴马大学伯明翰分校 (UAB) 将最先进的研究设施、优秀的职业发展资源和广泛的临床基础相结合，为培训医师科学家提供了理想的环境。该提案的基本假设是： 1) RSV 是原代人气道上皮细胞释放 MMP-9 的有效刺激物，并且 MMP-9 通过融合蛋白水解促进 RSV 在气道上皮细胞中的传播； 2) MMP-9促进RSV感染，并且是早期病毒引起的肺部炎症和损伤的调节剂； 3) RSV 诱导的呼吸衰竭儿科患者中 MMP-9 活性失调，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。候选人在获得职业发展奖期间的短期目标是完成本研究计划的目标，获得阿拉巴马大学临床和转化科学生物医学硕士学位，每年出席科学会议并提交五篇或更多同行评审出版物。在奖励期的后半段，她将提交独立R01资助的申请。她的长期目标是开发一个独立的研究项目，最终目标是在对基质破坏、气道和肺部炎症的深入了解的基础上，识别新的生物标志物并创造针对 RSV 疾病的新疗法，重点是宿主防御和宿主-病原体相互作用。