C3 Mitigates Epithelial Injury in Pneumonia

项目摘要 这项K08提案将加快首席调查员朝着成为一名 独立的内科医生兼科学家专注于开发创新疗法来改善肺炎的结果。 候选人：PI是华盛顿大学医学院(WUSM)的内科科学家。他完成了 肺部和重症监护医学研究员，获得临床研究理学硕士学位 来自WUSM，在天然免疫和呼吸道上皮细胞生物学的交叉点上开发专业知识 补体系统的世界权威约翰·阿特金森博士的指导。在阿特金森医生的指导下 在指导下，PI研究了细胞内蛋白质(特别是补体成分C3)如何调节 通过减轻应激诱导的细胞死亡来实现细胞反应。他将利用他在奖学金期间学到的技能 为了进一步分析C3作为一种细胞保护性疗法来降低肺炎严重程度，这是一个主要的未得到满足的需求。 职业发展计划：私家侦探将在他的主要导师阿特金森博士和联合 导师，Brody博士(呼吸道上皮细胞生物学专家)和Gelman博士(小鼠模型专家 肺损伤)，以及来自不同领域的一组壁内和壁外顾问。该委员会的所有成员 咨询团队在培养独立调查人员方面有相当丰富的经验。WUSM提供了一种高 优质的环境、优良的设施、资源和机会，以及一支协作的教职员工队伍。这 五年计划建立在PI先前经验的基础上，并填补了他培训中的空白，为他提供了工具 是独立所必需的。它包括以下目标：(1)掌握先进分子技术 生物学和免疫学(即小鼠的免疫表型)；(2)熟悉创新设计 使用肺损伤的临床前模型来改善肺炎预后的治疗；(3)定期介绍研究 在不同的场所，积极参与工作小组和协作；(4)提高指导技能；和(5) 每年至少出版一篇与该提案直接相关的手稿。 研究计划：该提议的科学前提是肺中的细胞内C3起着关键的保护作用 在肺炎中的作用，PI将通过两个具体目标进行测试。目标1将调查C3如何促进呼吸道 炎性应激条件下上皮细胞的存活。Aim 2将询问C3如何在局部发挥作用 肺可降低体内细菌性肺炎的严重程度。该计划是PI在以下方面变得方便的工具：(1) 调节细胞内通路对上皮细胞生存至关重要；(2)分析新开发的条件性 基因敲除小鼠，以确定肺部蛋白质的主要来源；以及(3)开发方法 在当地传递或增强这些蛋白质的生产，以减轻肺部疾病。完成目标将会 向PI提供适用于其他形式的肺损伤和上皮功能障碍的技能 其他障碍面。简而言之，当他成为一名无党派人士时，这一K08奖将支持他的科学生涯 他将专注于减轻肺部疾病的负担，与NHLBI的使命保持一致。

PROJECT ABSTRACT This K08 proposal will expedite the principal investigator’s progress towards his goal of becoming an independent physician-scientist focused on developing innovative therapies to improve pneumonia outcomes. Candidate: The PI is a physician-scientist at Washington University School of Medicine (WUSM). He completed a fellowship in Pulmonary and Critical Care Medicine and obtained a Master of Science in Clinical Investigation from WUSM, developing expertise at the intersection of innate immunity and airway epithelial cell biology under the mentorship of Dr. John Atkinson, a world authority on the complement system. Under Dr. Atkinson’s mentorship, the PI investigated how intracellular proteins (specifically, complement component C3) modulate cellular responses by mitigating stress-induced cell death. He will leverage the skills gained during his fellowship to further analyze C3 as a cytoprotective therapeutic for reducing pneumonia severity, a major unmet need. Career Development Plan: The PI will execute this proposal under his primary mentor, Dr. Atkinson and co- mentors, Dr. Brody (an expert in airway epithelial cell biology) and Dr. Gelman (an expert in mouse models of lung injury) along with a team of intramural and extramural advisors from diverse fields. All members of the advisory team have considerable experience in nurturing independent investigators. WUSM provides a high- quality environment with excellent facilities, resources and opportunities, as well as a collaborative faculty. This 5-year plan builds on the PI’s prior experience and fills in the gaps in his training, providing him with the tools needed for independence. It includes the following objectives: (1) Master techniques in advanced molecular biology and immunology (i.e., immunophenotyping of mice); (2) Become familiar with designing innovative therapies to improve pneumonia outcomes using preclinical models of lung injury; (3) Present research regularly in diverse venues, actively participate in working groups and collaborate; (4) Enhance mentoring skills; and (5) Publish at least 1 manuscript per year directly related to this proposal. Research Plan: The scientific premise of the proposal is that intracellular C3 in the lung plays a critical protective role in pneumonia, which the PI will test via two Specific Aims. Aim 1 will investigate how C3 promotes airway epithelial cell survival during inflammatory stress in vitro. Aim 2 will interrogate how locally functioning C3 in the lung reduces bacterial pneumonia severity in vivo. The plan is a vehicle for the PI to become facile in: (1) modulating intracellular pathways important for epithelial cell survival; (2) analyzing newly developed conditional knockout mice to ascertain the predominant sources of proteins in the lungs; and (3) developing approaches to deliver or enhance the production of these proteins locally to alleviate lung disease. Completing the Aims will provide the PI with the skills that are readily applicable to other forms of lung injury, and epithelial dysfunction at other barrier surfaces. In short, this K08 award will bolster his scientific career as he becomes an independent investigator who will focus on reducing the burden of pulmonary diseases, in alignment with the NHLBI mission.