Program to promote lung regeneration and block fibrosis
促进肺再生和阻止纤维化的计划
基本信息
- 批准号:9893639
- 负责人:
- 金额:$ 96.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AlveolarAnimal ModelAttenuatedAutomobile DrivingBiopsyCellsClinicClinical TrialsDataDiagnosticDiseaseEnvironmentEpigallocatechin GallateEpithelialEpitheliumFailureFibroblastsFibrosisFunctional disorderFundingFutureGoalsHealthHumanInjuryLOXL2 geneLungLung TransplantationLung diseasesMesenchymalMorbidity - disease rateMusNatural regenerationOrganoidsPathway interactionsPatientsProcessPulmonary FibrosisResearchTestingTimeTissuesType II Epithelial Receptor Cellbasecytokineepithelial injuryepithelium regenerationfibrogenesisimprovedin vivoinhibitor/antagonistlung regenerationmolecular imagingmortalitynovel therapeutic interventionprogenitorprogramssingle-cell RNA sequencingsmall moleculestemstem cellstissue biomarkers
项目摘要
ABSTRACT
The goal of this research program is to understand the interactions between lung epithelial and mesenchymal
cells in sufficient detail to deliver new therapeutic interventions in pulmonary fibrosis, a process without disease
modifying therapies. This program is anchored by a recently funded RO1 to further elucidate mechanisms of a
fibroblast-specific trihydroxyphenolic inhibitor of LOXL2 and TGFR1 with potent in vivo anti-fibrotic effects. We
will test one of these, EGCG, in a proof of principle clinical trial. Unpublished data show reversal of a core set
of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy. The
R35 mechanism allows us to integrate our capacity to attenuate fibrosis with the broader issue of defective
epithelial regeneration in IPF, a competing process with fibrogenesis. This is sometimes simplified in the idea
repeated epithelial injury leads to stem cell failure thereby creating an unrelenting pro-fibrotic environment. But
the lung is resilient with multiple, spatially distinct progenitor cells whose identify and integrative functions
remain poorly understood, especially in IPF patients. This paradigm also overlooks the potentially critical
contribution of pro-fibrotic mesenchymal cells in driving further loss of the epithelium. Type II cells in the IPF
lung at the time of lung transplant are less than 15% of that present in a normal lung. The program will focus
on further elucidating the potential of resident epithelial stem/progenitors in mouse and human to regenerate
alveolar integrity. In parallel, mechanisms by which activated mesenchymal cells contribute to dysfunction and
loss of these epithelial progenitors will be defined. We plan to leverage fibroblast-specific TGFb1 inhibition to
study its impact on progenitor cells in both animal models and in IPF patients, for example by single cell RNA-
seq of tissues from untreated and EGCG treated patients. We envision a future small molecule image-based
screen to identify agents that improve type II cell health in cultured epithelial/fibroblast organoids. Overall the
R35 program gives us the opportunity to integrate all of these directions into a centrally themed,
multidimensional approach that should transform how we view lung regeneration and fibrogenesis and how we
treat patients with unrelenting fibrosis.
摘要
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:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 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:
9355470 - 财政年份:2016
- 资助金额:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 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:
$ 96.55万 - 项目类别:
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