Lung-derived complement in pneumonia
肺炎中的肺源性补体
基本信息
- 批准号:10568567
- 负责人:
- 金额:$ 54.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-19 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAcute PneumoniaAddressAnabolismAreaAttenuatedBacteremiaBacteriaBacterial InfectionsBacterial PneumoniaBindingBiochemicalBiological AssayBronchopneumoniaCRISPR screenCause of DeathCell DeathCell Death InductionCell SurvivalCell secretionCellsCessation of lifeCirculationClustered Regularly Interspaced Short Palindromic RepeatsComplementComplement 3 ConvertaseComplement 3aComplement 3bComplement ActivationComplement Factor BCytoprotectionDataDepositionEnzymesEpithelial CellsEpitheliumGene DeliveryGeneticGoalsHost DefenseHost Defense MechanismHumanImmune responseIn VitroIndividualInfectionInflammatory ResponseKnock-outKnowledgeLibrariesLigandsLiquid substanceLiverLungMediatingModelingMolecularMorbidity - disease rateMucous MembraneMusNational Heart, Lung, and Blood InstitutePathway interactionsPatternPlasmidsPneumoniaPredispositionProteinsProteomicsPseudomonas aeruginosaPseudomonas aeruginosa infectionPseudomonas aeruginosa pneumoniaReportingResearchResearch PriorityRoleSeveritiesSiteSourceStressStructure-Activity RelationshipSurfaceTestingTissuesTransfectionTransgenic MiceWorkairway epitheliumalveolar epitheliumarmcell injurycellular imagingcomplement systemdesigngene therapyhuman modelhumoral immunity deficiencyimprovedin vivoknowledge integrationlung injurymortalitymouse modelmutantnovelnovel therapeuticsoverexpressionoxidant stresspathogenpathogenic bacteriapharmacologicpneumonia treatmentprotective effectprotein transportpulmonary functionreceptorresilienceuptakeworking group
项目摘要
PROJECT ABSTRACT
The objective of this R01 proposal is to investigate the function of lung-derived complement proteins and harness
their activities to mitigate the severity of pneumonia. Complement proteins C3 and Factor B (FB) comprise an
early arm of the host immune response. They are primarily derived from the liver and function in the circulation
by killing pathogens such as bacteria. However, our recent work has demonstrated the importance of local C3
expression in lung epithelial cell survival during stress. This proposal focuses on an emerging role for lung-
derived FB, a ligand for C3, in reducing excessive tissue damage in the setting of an acute bacterial pneumonia.
Our goal is to determine how FB promotes pulmonary host defense. We will investigate sources of FB in the
lung and establish its putative protective effect relative to C3. A major hurdle for investigating tissue-specific
roles of complement has been the limited availability of models and assays. We have developed novel transgenic
mouse models and functional assays that distinguish the roles of liver- and lung-derived complement proteins,
and specifically identify the role of lung-derived FB in pneumonia. Our mouse models are supplemented with
data from in vitro human models that demonstrate the role of FB to protect against stress-induced epithelial cell
death. Additionally, CRISPR-induced deletion of cell-derived complement proteins suggests active
internalization of exogenous complement proteins. These combined results support our central hypothesis that
lung-derived FB promotes host defense by mitigating epithelial cell death. This proposal will test our
hypothesis by achieving two Specific Aims. Aim 1 compares global FB-deficient, targeted liver FB-deficient, and
lung epithelial cell-derived FB-deficient mice to assess how lung-derived FB mitigates acute bronchopneumonia
severity and cell death. We also will assess if augmenting FB in the lung using pharmacological and gene delivery
approaches protects against pneumonia. Aim 2 analyzes whether lung-derived, intracellular FB activity mitigates
cell death in vitro by leveraging a combination of human primary lung epithelial cells and FB-deficient cells to
dissect the molecular and biochemical mechanisms responsible for complement function in the lung. The
proposal integrates knowledge of pulmonary complement activation, intracellular complement protein trafficking,
and structure-function relationships with gene therapy, cell imaging, proteomics, and CRISPR screens to
determine how lung-derived FB promotes epithelial cytoprotection during stress. These approaches are
independent but complementary for investigating the immunobiological role of lung-derived FB in mucosal barrier
protection of the lung. The proposed work is important because understanding how the early host immune
response modulates tissue damage is essential for designing and implementing urgently needed, new therapies
for pneumonia. Thus, we will assess how lung-derived FB facilitates host defense at the site of infection and
promotes tissue resilience. These efforts will help our long-term goal of developing a novel host-focused therapy
for pneumonia, thus aligning with a priority area of the NHLBI Working Group Report on pneumonia research.
项目摘要
这个R01提案的目的是研究肺源性补体蛋白的功能和利用
他们的活动,以减轻肺炎的严重性。补体蛋白C3和B因子(Fb)包括
手臂早期对宿主的免疫反应。它们主要来源于肝脏,在血液循环中起作用。
通过杀死细菌等病原体。然而,我们最近的工作证明了本地C3的重要性
应激状态下肺上皮细胞存活的表达。这项提议的重点是肺的一个新兴角色-
衍生的Fb,C3的配体,在急性细菌性肺炎的背景下减少过度的组织损伤。
我们的目标是确定FB是如何促进肺宿主防御的。我们将调查FB的来源
并确定其相对于补体C3的假定保护作用。研究组织特异性的主要障碍
补充物的作用一直是模型和分析的有限可获得性。我们开发出了新的转基因技术
小鼠模型和区分肝脏和肺来源的补体蛋白作用的功能分析,
并具体确定肺源性FB在肺炎中的作用。我们的小鼠模型补充了
来自体外人类模型的数据显示了FB对应激诱导的上皮细胞的保护作用
死亡。此外,CRISPR诱导的细胞衍生补体蛋白的缺失表明是活性的
外源补体蛋白的内化。这些综合结果支持我们的中心假设
肺源性FB通过减轻上皮细胞死亡来促进宿主防御。这项提议将考验我们的
通过实现两个具体目标来实现假设。目的1比较全球Fb缺陷、靶向肝脏Fb缺陷和
肺上皮细胞来源的Fb缺陷小鼠评估肺来源的Fb如何减轻急性支气管炎
严重程度和细胞死亡。我们还将评估是否通过药物和基因传递来增加肺中的Fb
Approach预防肺炎。目的2分析肺来源的细胞内Fb活性是否减轻
利用人原代肺上皮细胞和FB缺陷细胞的组合在体外诱导细胞死亡
剖析肺内补体功能的分子和生化机制。这个
该方案整合了肺补体激活、细胞内补体蛋白运输、
以及与基因治疗、细胞成像、蛋白质组学和CRISPR筛查的结构-功能关系
确定肺源性FB如何在应激状态下促进上皮细胞保护。这些方法是
独立但互补研究肺源性FB在粘膜屏障中的免疫生物学作用
对肺的保护。这项拟议的工作很重要,因为了解早期宿主如何免疫
反应调节组织损伤是设计和实施迫切需要的新疗法的关键
治疗肺炎。因此,我们将评估肺源性FB如何促进感染部位的宿主防御和
促进组织弹性。这些努力将有助于我们开发一种以宿主为重点的新疗法的长期目标
对于肺炎,因此与NHLBI工作组关于肺炎研究的报告的优先领域一致。
项目成果
期刊论文数量(0)
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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:
$ 54.37万 - 项目类别:
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