Matrix Metalloproteinase Driven Lung Inflammation in RSV disease

描述(由申请人提供)：这份建议书描述了一个为期5年的指导培训计划，为候选人Michele Kong博士提供关于炎症的细胞和分子机制、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的强化培训，这将有助于她成为一名独立的研究人员。孔博士在学术成就和致力于研究事业方面有着长期的记录。在她的职业发展和研究活动中，孔博士将得到J.Edwin Blalock博士和Amit Gaggar医学博士的指导，他们是免疫学、炎症和蛋白酶生物学方面的公认领导者。孔博士还组建了一个在炎症、传染病和翻译研究领域具有专业知识的顾问委员会(Rich Whitley博士、Namasivayam Ambalavanan博士、Eric Sorscher博士和JP Clancy博士)，他们都承诺成功完成拟议的研究目标，并帮助她过渡到一名独立的内科科学家。阿拉巴马大学伯明翰分校(UAB)结合了最先进的研究设施、出色的职业发展资源和广泛的临床基础，为培养内科科学家提供了理想的环境。该建议的基本假设是：1)呼吸道合胞病毒可有效刺激原代人呼吸道上皮细胞释放基质金属蛋白酶-9，而基质金属蛋白酶-9通过融合蛋白的降解促进呼吸道合胞病毒在呼吸道上皮细胞中的传播；2)基质金属蛋白酶-9促进呼吸道合胞病毒感染，并是病毒诱导的早期肺部炎症和损伤的调节因子；3)在呼吸道合胞病毒引起的呼吸衰竭的儿科患者中，基质金属蛋白酶-9活性调节失调，直接与下游趋化性PGP片段的产生和疾病严重程度的临床指标相关。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，在UAB获得临床和翻译科学方面的生物医学硕士学位，每年在科学会议上发表演讲，并提交五本或更多同行评议的出版物。在获奖期的后半部分，她将提交独立R01资金申请。她的长期目标是开发一个独立的研究计划，最终目标是识别新的生物标记物，并基于对基质破坏、呼吸道和肺部炎症的更好理解，创造治疗RSV疾病的新疗法，重点是宿主防御和宿主与病原体的相互作用。

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.