Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
基本信息
- 批准号:9355470
- 负责人:
- 金额:$ 94.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-21 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAcuteAcute Lung InjuryAcute respiratory failureAddressAdult Respiratory Distress SyndromeAlveolarAlveolar Cell Type IApoptosisAreaCell Differentiation processCellsChronicClinicalCytokeratin 17DevelopmentDiffuseDistalEndothelial CellsEngraftmentEpithelialEpithelial CellsEquilibriumGasesGenesGoalsGraft SurvivalHistologyHomeostasisHumanHypoxiaImmunosuppressionIn VitroInfluenzaInjection of therapeutic agentInjuryLeadLungLung diseasesMacacaMethodologyModelingMolecularMonkeysMusNatural regenerationNecrosisOrganPathway interactionsPharmacologyPhasePrimatesProcessProtocols documentationPulmonary Surfactant-Associated Protein CPulmonologyReplacement TherapyReportingResearch PersonnelRespiratory physiologySignal TransductionStem cellsStressSupportive careSurfaceTestingTherapeuticToxic effectTranslationsTransplantationType II Epithelial Receptor CellUndifferentiatedcapillary bedcell motilityexperimental studyfunctional improvementimprovedin vivoinduced pluripotent stem cellinjury and repairlung hypoxialung injurylung repairmigrationmouse modelnotch proteinnovel therapeutic interventionprogenitorprogramsregenerativerepairedscreeningself-renewalstemtooltranslation to humans
项目摘要
ABSTRACT
The overall goal of this application is to develop a compelling rationale and workable methodology for the
treatment of diffuse alveolar damage with transplanted human epithelial stem/progenitor cells capable of long
term engraftment and improved organ function. Stem/progenitor replacement therapy is envisioned as a
meaningful therapeutic adjunct in several clinical situations dominated by diffuse alveolar damage with
epithelial loss: severe, acute lung injury, e.g. due to influenza or other causes of ARDS, as well as acute
exacerbations of chronic fibrotic lung disease. Recent studies discussed in the application indicate effective
alveolar regeneration, and thus improved lung function, requires both a first phase of expansion and migration
of stem/progenitor cells to re-establish alveolar barriers followed by a second phase of differentiation of new
barrier cells into mature type II (AEC2s) and type I alveolar cells. To develop a translational program for
alveolar regeneration by transplantation of healthy lung epithelial stem/progenitor cells, three basic objectives
are advanced: (1) Further delineation of the signaling programs by which endogenous human distal lung
epithelial stem cells can be activated following major injury to establish new alveolar barriers and then
differentiate to AEC2s. (2) In vitro development of pools of human distal (small airway and alveolar) epithelial
stem cells, both endogenous and iPSC-derived, suitable for transplantation and directed differentiation in mice.
Distal basal-like cells from human iPS cells using gene edited cells reporting surfactant protein C, cytokeratin
17 (Krt17), and NKX2.1 will be used to develop a workable protocol for directed differentiation after transplant.
(3) Employ models of lung repair/regeneration approachable by transplantation as tools to assess the
regenerative potential of human epithelial stem/progenitor cells. Macaque iPS cells suitable for
transplantation into influenza-infected monkeys will be used as a primate model for therapy. It is anticipated
that functional improvement in gas exchange and alveolar histology can be achieved in primates, providing
both a rationale and methodology for stem/progenitor cells as adjunctive therapy after severe acute lung injury
in humans.
摘要
本申请的总体目标是为以下方面开发一个令人信服的基本原理和可行的方法:
移植的人上皮干/祖细胞治疗弥漫性肺泡损伤
长期移植和改善器官功能。干/祖细胞替代疗法被设想为一种
在以弥漫性肺泡损伤为主的几种临床情况下,
上皮损失:严重的急性肺损伤,例如由于流感或其他原因的ARDS,以及急性
慢性纤维化肺病的恶化。在申请中讨论的最新研究表明,
肺泡再生,从而改善肺功能,需要扩张和迁移的第一阶段
干/祖细胞重建肺泡屏障,然后是新的细胞分化的第二阶段。
屏障细胞分化为成熟的II型(AEC 2)和I型肺泡细胞。开发一个翻译程序
通过移植健康肺上皮干/祖细胞实现肺泡再生,三个基本目标
(1)进一步阐明了内源性人远端肺细胞凋亡的信号程序,
上皮干细胞可在严重损伤后被激活以建立新的肺泡屏障,
区别于AEC 2。(2)人远端(小气道和肺泡)上皮细胞池的体外发育
干细胞,包括内源性和iPSC衍生的干细胞,适用于小鼠移植和定向分化。
使用报告表面活性蛋白C、细胞角蛋白的基因编辑的细胞,来自人iPS细胞的远端基底样细胞
17(Krt 17)和NKX2.1将用于开发移植后定向分化的可行方案。
(3)采用可通过移植实现的肺修复/再生模型作为评估
人上皮干/祖细胞的再生潜力。猕猴iPS细胞适用于
移植到流感感染的猴子中的细胞将用作治疗的灵长类动物模型。预计
在灵长类动物中可以实现气体交换和肺泡组织学的功能改善,
干/祖细胞作为严重急性肺损伤后连续治疗的理论基础和方法学
在人类身上。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Harold A Chapman其他文献
Harold A Chapman的其他文献
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{{ truncateString('Harold A Chapman', 18)}}的其他基金
Phase 1 study of oral epigallocatechin-3-gallate (EGCG) in IPF patients
IPF 患者口服表没食子儿茶素-3-没食子酸酯 (EGCG) 的 1 期研究
- 批准号:
10702133 - 财政年份:2022
- 资助金额:
$ 94.83万 - 项目类别:
Phase 1 study of oral epigallocatechin-3-gallate (EGCG) in IPF patients
IPF 患者口服表没食子儿茶素-3-没食子酸酯 (EGCG) 的 1 期研究
- 批准号:
10418169 - 财政年份:2022
- 资助金额:
$ 94.83万 - 项目类别:
Program to promote lung regeneration and block fibrosis
促进肺再生和阻止纤维化的计划
- 批准号:
9893639 - 财政年份:2020
- 资助金额:
$ 94.83万 - 项目类别:
Program to promote lung regeneration and block fibrosis
促进肺再生和阻止纤维化的计划
- 批准号:
10570862 - 财政年份:2020
- 资助金额:
$ 94.83万 - 项目类别:
Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
- 批准号:
10181019 - 财政年份:2016
- 资助金额:
$ 94.83万 - 项目类别:
Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage
上皮干/祖细胞作为弥漫性肺泡损伤的修复剂
- 批准号:
10418711 - 财政年份:2016
- 资助金额:
$ 94.83万 - 项目类别:
Epithelial Stem/Progenitor Cells in Repair of the Injured Lung
上皮干细胞/祖细胞修复受损肺
- 批准号:
9109038 - 财政年份:2015
- 资助金额:
$ 94.83万 - 项目类别:
Identification, Isolation, and Reprogramming Alveolar Epithelial Progenitor Cells
肺泡上皮祖细胞的鉴定、分离和重编程
- 批准号:
7676645 - 财政年份:2008
- 资助金额:
$ 94.83万 - 项目类别:
Urokinase Receptor Integrin Interactions in Lung Cancer
肺癌中尿激酶受体整合素相互作用
- 批准号:
7318124 - 财政年份:2007
- 资助金额:
$ 94.83万 - 项目类别:
Urokinase Receptor Integrin Interactions in Lung Cancer
肺癌中尿激酶受体整合素相互作用
- 批准号:
8079454 - 财政年份:2007
- 资助金额:
$ 94.83万 - 项目类别:
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