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
• 负责人: Harold A Chapman
• 金额: $ 96.55万
• 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/9893639
• 关键词: Alveolar; Animal Model; Attenuated; Automobile Driving; Biopsy; Cells; Clinic; Clinical Trials; Data; Diagnostic; Disease; Environment; Epigallocatechin Gallate; Epithelial; Epithelium; Failure; Fibroblasts; Fibrosis; Functional disorder; Funding; Future; Goals; Health; Human; Injury; LOXL2 gene; Lung; Lung Transplantation; Lung diseases; Mesenchymal; Morbidity - disease rate; Mus; Natural regeneration; Organoids; Pathway interactions; Patients; Process; Pulmonary Fibrosis; Research; Testing; Time; Tissues; Type II Epithelial Receptor Cell; base; cytokine; epithelial injury; epithelium regeneration; fibrogenesis; improved; in vivo; inhibitor/antagonist; lung regeneration; molecular imaging; mortality; novel therapeutic intervention; progenitor; programs; 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 Unpublished data show reversal of a core set of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy.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.

摘要 这项研究的目标是了解肺上皮和间充质之间的相互作用。 足够详细的细胞来提供新的肺纤维化治疗干预措施，这是一个没有疾病的过程 修改治疗方法。该程序由最近资助的RO1支持，以进一步阐明 成纤维细胞特异性的三羟基酚抑制剂LOXL2和TGFR1在体内具有强大的抗纤维化作用。我们 将在一项原则证明临床试验中测试其中一种EGCG。未公布的数据显示核心集合的反转 在诊断肺活检前两周服用EGCG的IPF患者中促纤维化组织生物标志物的变化。这个 R35机制使我们能够将我们减轻纤维化的能力与更广泛的缺陷问题结合起来 IPF中的上皮再生是与纤维化形成竞争的过程。这有时在思想上被简化了 反复的上皮损伤会导致干细胞衰竭，从而创造一个无情的促纤维化环境。但 肺具有弹性，有多个在空间上不同的祖细胞，它们具有识别和整合功能。 仍然知之甚少，尤其是在IPF患者中。这种范式也忽略了潜在的关键 促纤维化间充质细胞在推动上皮进一步丧失中的作用。IPF中的II型细胞 肺移植时的肺活量不到正常肺的15%。该计划将重点放在 关于进一步阐明小鼠和人体内常驻上皮干/祖细胞再生潜力的研究 牙槽骨完整。同时，激活的间充质细胞促进功能障碍和 这些上皮祖细胞的丧失将被定义。我们计划利用成纤维细胞特异性的TGFb1抑制来 在两种动物模型和IPF患者中研究其对祖细胞的影响，例如通过单细胞RNA- 对未经治疗和EGCG治疗的患者的组织进行SEQ。我们展望了未来基于图像的小分子 筛选出在培养的上皮/成纤维细胞类器官中改善II型细胞健康的药物。总体而言 R35计划让我们有机会将所有这些方向整合到一个中心主题中， 多维方法应该改变我们看待肺再生和纤维化的方式以及我们如何 治疗患有顽固性纤维化的患者。