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
• 负责人: Harold A Chapman
• 金额: $ 96.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10570862
• 关键词: Alveolar; Animal Model; Attenuated; Automobile Driving; Biopsy; Cells; Clinic; Clinical Trials; Data; Diagnostic; Dimensions; Disease; Environment; Epigallocatechin Gallate; Epithelium; Failure; Fibroblasts; Fibrosis; Functional disorder; Funding; Future; Goals; Health; Human; Injury; LOXL2 gene; Lung; Lung Transplantation; Lung fibrogenesis; Mesenchymal; Morbidity - disease rate; Mus; Natural regeneration; Organoids; Pathway interactions; Patients; Process; Pulmonary Fibrosis; Research; Testing; Time; Tissues; Transforming Growth Factor beta; Type II Epithelial Receptor Cell; cytokine; epithelial injury; epithelium regeneration; fibrogenesis; fibrotic lung disease; improved; in vivo; inhibitor; lung regeneration; molecular imaging; mortality; novel therapeutic intervention; progenitor; programs; resilience; single-cell RNA sequencing; small molecule; stem; stem cells; tissue biomarkers

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 Unpublished data show reversal of a core set of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy.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.

抽象的 该研究计划的目的是了解肺上皮和间质之间的相互作用 细胞足够详细地提供肺纤维化的新治疗干预措施，这是没有疾病的过程 修改疗法。该程序由最近资助的RO1锚定，以进一步阐明 LOXL2和TGFR1的成纤维细胞特异性三羟基苯酚抑制剂具有有效的体内抗纤维化作用。我们 将在原则临床试验的证明中测试其中一个EGCG。未发表的数据显示核心集的逆转 IPF患者的促纤维化组织生物标志物在诊断性肺活检前两周给予EGCG。这 R35机制使我们能够将减弱纤维化的能力与更广泛的缺陷问题相结合 IPF中的上皮再生，这是一种具有纤维化的竞争过程。这有时可以在想法中简化 重复的上皮损伤导致干细胞衰竭，从而产生一个不屈不挠的促纤维化环境。但 肺具有弹性，具有多个空间不同的祖细胞，其识别和整合功能 保持不当理解，尤其是在IPF患者中。这个范式也忽略了潜在的关键 促纤维性间充质细胞在推动上皮进一步丧失方面的贡献。 IPF中的II型单元格 肺移植时的肺少于正常肺中存在的肺部。该计划将集中 进一步阐明了小鼠和人类中居民上皮茎/祖细胞的潜力 牙槽完整性。同时，活化间充质细胞的机制有助于功能障碍和 这些上皮祖细胞的丢失将被定义。我们计划利用成纤维细胞特异性的TGFB1抑制作用 研究其对动物模型和IPF患者中祖细胞的影响，例如单细胞RNA- 来自未治疗和EGCG治疗的患者的组织SEQ。我们设想未来的基于图像的小分子 筛选以鉴定改善培养的上皮/成纤维细胞器官中II型细胞健康的药物。总体而言 R35计划使我们有机会将所有这些方向集成到一个以中心为主题的主题中， 多维方法应该改变我们如何看待肺部再生和纤维化以及我们的方式 治疗无抗纤维化的患者。