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C3 Mitigates Epithelial Injury in Pneumonia

C3 减轻肺炎中的上皮损伤

基本信息

批准号：
10473517
负责人：
Hrishikesh Satish Kulkarni
金额：
$ 14.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473517
关键词：
Address Advisory Committees Albumins Anti-Bacterial Agents Antibiotics Attenuated Award Bacteremia Bacteria Bacterial Pneumonia Binding Caspase Cause of Death Cell Death Cell Line Cell Survival Cells Cellular Stress Cellular Stress Response Cellular biology Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Complement Complement 3a Complement 3b Critical Care Data Development Plans Environment Epithelial Epithelial Cells Extracellular Space Extrahepatic Extramural Activities FRAP1 gene Faculty Fellowship Functional disorder Future Generations Genetic Goals Histology Hospitalization Host Defense Human Immune Immune response Immunophenotyping In Vitro Incubated Infection Infection Control Inflammation Inflammatory Injury Innate Immune Response Innovative Therapy Kinetics Knockout Mice Knowledge Lead Liquid substance Liver Cirrhosis LoxP-flanked allele Lung Lung Transplantation Lung diseases MAPK3 gene Manuscripts Master of Science Measures Mediating Medicine Mentors Mentorship Mission Molecular Biology Molecular Immunology Molecular Target Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Natural Immunity Outcome Oxidative Stress Pathway interactions Patients Peptide Hydrolases Pharmacology Phase Physicians Plasma Play Pneumonia Pre-Clinical Model Principal Investigator Production Proteins Pseudomonas Publishing Research Research Personnel Resources Role Scientist Serum Severities Site Source Stress Surface Techniques Testing Therapeutic Training United States Universities Vascular Permeabilities Washington Wild Type Mouse airway epithelium authority career career development cell injury cell type clinical investigation cobra venom factor complement C3 precursor complement system conditional knockout cytokine design epithelial injury experience fighting improved in vivo injury and repair lung injury medical schools member mortality mortality risk mouse model novel programs receptor response skills stressor therapeutic candidate tool transcriptome sequencing transplant model uptake working group

项目摘要

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.

项目摘要这项 K08 提案将加快首席研究员实现成为一名独立医师科学家专注于开发创新疗法以改善肺炎结果。候选人：PI 是华盛顿大学医学院 (WUSM) 的一名医师兼科学家。他完成了获得肺科和重症监护医学奖学金并获得临床研究理学硕士学位来自 WUSM，在先天免疫和气道上皮细胞生物学交叉领域开发专业知识补体系统世界权威 John Atkinson 博士的指导。在阿特金森博士的指导下在指导下，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调节细胞反应。他将利用在奖学金期间获得的技能进一步分析 C3 作为一种细胞保护疗法，可降低肺炎严重程度，这是一个未满足的主要需求。职业发展计划：PI 将在他的主要导师 Atkinson 博士和同事的指导下执行此建议导师：Brody 博士（气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校内和校外顾问团队。全体成员顾问团队在培养独立调查人员方面拥有丰富的经验。 WUSM 提供了高优质的环境，优良的设施、资源和机会，以及协作的教师队伍。这 5 年计划以 PI 之前的经验为基础，填补了他的培训空白，为他提供了工具独立所需。它包括以下目标：（1）掌握先进分子技术生物学和免疫学（即小鼠的免疫表型分析）； (2)熟悉设计创新使用肺损伤的临床前模型改善肺炎结果的疗法；（三）定期开展研究在不同的场所，积极参与工作组并进行协作； (4) 提高指导能力；和（5）每年至少发表 1 篇与本提案直接相关的手稿。研究计划：该提案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 将研究 C3 如何促进气道体外炎症应激期间上皮细胞的存活。目标 2 将询问 C3 在本地的运作方式肺可降低体内细菌性肺炎的严重程度。该计划是 PI 轻松实现以下目标的工具：(1) 调节对上皮细胞存活很重要的细胞内途径； (2) 分析新开发的条件基因敲除小鼠以确定肺部蛋白质的主要来源； (3) 制定方法局部递送或增强这些蛋白质的产生以减轻肺部疾病。完成目标将为 PI 提供可轻松应用于其他形式的肺损伤和上皮功能障碍的技能其他障碍表面。简而言之，随着他成为一名独立的科学家，这个 K08 奖项将支持他的科学事业调查员将致力于减轻肺部疾病的负担，与 NHLBI 的使命保持一致。