C3 Mitigates Epithelial Injury in Pneumonia
C3 减轻肺炎中的上皮损伤
基本信息
- 批准号:10687247
- 负责人:
- 金额:$ 11.1万
- 依托单位:
- 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:
- 关键词:Advisory CommitteesAlbuminsAnti-Bacterial AgentsAntibioticsAttenuatedAuthorization documentationAwardBacteremiaBacteriaBacterial PneumoniaBindingCaspaseCause of DeathCell DeathCell Death InductionCell LineCell SurvivalCellsCellular StressCellular biologyCessation of lifeClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplementComplement 3aComplement 3bCritical CareCytoprotectionDataDevelopment PlansEnvironmentEpithelial CellsEpitheliumExtracellular SpaceExtrahepaticExtramural ActivitiesFRAP1 geneFacultyFellowshipFunctional disorderFutureGenerationsGeneticGoalsHistologyHospitalizationHost DefenseHumanImmuneImmune responseImmunophenotypingIn VitroIncubatedInfectionInfection ControlInflammationInflammatoryInjuryInnate Immune ResponseInnovative TherapyKineticsKnockout MiceKnowledgeLiquid substanceLiver CirrhosisLoxP-flanked alleleLungLung TransplantationLung diseasesMAPK3 geneManuscriptsMaster of ScienceMeasuresMediatingMedicineMentorsMentorshipMissionMolecular BiologyMolecular ImmunologyMolecular TargetMorbidity - disease rateMusNational Heart, Lung, and Blood InstituteNatural ImmunityOutcomeOxidative StressPathway interactionsPatientsPeptide HydrolasesPhasePhysiciansPlasmaPlayPneumoniaPre-Clinical ModelPrincipal InvestigatorProductionProteinsPseudomonasPublishingResearchResearch PersonnelResourcesRoleScientistSerumSeveritiesSiteSourceStressSurfaceTechniquesTestingTherapeuticTrainingUnited StatesUniversitiesVascular PermeabilitiesVasodilationWashingtonWild Type Mouseairway epitheliumauthoritycareercareer developmentcell injurycell typeclinical investigationcobra venom factorcomplement C3 precursorcomplement systemconditional knockoutcytokinedesignepithelial injuryepithelial repairexperiencefightingimprovedin vivolung injurymedical schoolsmembermortalitymortality riskmouse modelnovelpharmacologicprogramsreceptorresponseskillsstress reductionstressortherapeutic candidatetooltranscriptome sequencingtransplant modeluptakeworking 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
本K 08提案将加快主要研究者的进度,以实现其成为
独立的医生-科学家专注于开发创新疗法,以改善肺炎的结果。
候选人:PI是华盛顿大学医学院(WUSM)的一名医生兼科学家。他完成
肺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的交叉点上发展专业知识,
约翰·阿特金森博士的指导,他是补体系统的世界权威。在阿特金森医生的
在导师的指导下,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减轻细胞反应。他将利用在研究期间获得的技能
进一步分析C3作为降低肺炎严重程度的细胞保护性治疗剂,这是一个主要的未满足需求。
职业发展计划:PI将在他的主要导师Atkinson博士和合作伙伴的指导下执行该计划。
Brody博士(气道上皮细胞生物学专家)和Gelman博士(
肺损伤)沿着的是来自不同领域的校内和校外顾问团队。所有成员
顾问团队在培养独立调查人员方面经验丰富。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。这
5-一年计划建立在PI先前的经验之上,填补了他在培训中的空白,为他提供了工具
需要独立。主要包括以下几个方面的内容:(1)掌握先进的分子生物学技术
生物学和免疫学(即,小鼠免疫表型);(2)熟悉设计创新
使用肺损伤的临床前模型改善肺炎结局的治疗;(3)定期开展研究
在不同的场合,积极参与工作组和合作;(4)提高指导技能;和(5)
每年至少出版一份与本提案直接相关的稿件。
研究计划:该提案的科学前提是,细胞内C3在肺中起着关键的保护作用。
主要研究者将通过两个特定目的测试肺炎中的作用。目的1将研究C3如何促进气道
体外炎症应激期间上皮细胞存活。目标2将询问C3如何在局部运作,
肺降低体内细菌性肺炎的严重程度。该计划是PI在以下方面变得容易的工具:(1)
调节对上皮细胞存活重要的细胞内途径;(2)分析新开发的条件性
基因敲除小鼠,以确定肺中蛋白质的主要来源;以及(3)开发方法,
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提供易于适用于其他形式的肺损伤和上皮功能障碍的技能,
其他障碍物。简而言之,这个K 08奖将支持他的科学生涯,因为他成为一个独立的
研究人员将专注于减少肺部疾病的负担,与NHLBI的使命保持一致。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Role of Complement Component C3 in Protection Against Pseudomonas Pneumonia-Induced Lung Injury.
补体成分 C3 在预防假单胞菌肺炎引起的肺损伤中的作用。
- DOI:10.1089/dna.2023.0445
- 发表时间:2024
- 期刊:
- 影响因子:3.1
- 作者:Sahu,SanjayaK;Maurya,RahulK;Kulkarni,HrishikeshS
- 通讯作者:Kulkarni,HrishikeshS
Targeting complement activation in COVID-19.
- DOI:10.1182/blood.2020008925
- 发表时间:2020-10-29
- 期刊:
- 影响因子:20.3
- 作者:Kulkarni HS;Atkinson JP
- 通讯作者:Atkinson JP
Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.
- DOI:10.1016/s2213-2600(23)00082-6
- 发表时间:2023-12
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Hrishikesh Satish Kulkarni其他文献
Hrishikesh Satish Kulkarni的其他文献
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{{ truncateString('Hrishikesh Satish Kulkarni', 18)}}的其他基金
Lung epithelial cell-derived C3 in acute lung injury
肺上皮细胞衍生的 C3 在急性肺损伤中的作用
- 批准号:
10720687 - 财政年份:2023
- 资助金额:
$ 11.1万 - 项目类别:
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