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 Unpublished data show reversal of a core set of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy.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 该研究计划的目标是了解肺上皮细胞和间充质细胞之间的相互作用 足够详细的细胞以对肺纤维化（一个没有疾病的过程）提供新的治疗干预措施 修改疗法。该计划以最近资助的 RO1 为基础，旨在进一步阐明 LOXL2 和 TGFR1 的成纤维细胞特异性三羟基酚抑制剂，具有有效的体内抗纤维化作用。我们 将在原则性临床试验中测试其中的一种，即 EGCG。未发表的数据显示核心组的逆转 在诊断性肺活检前两周给予 EGCG 的 IPF 患者促纤维化组织生物标志物的研究。这 R35 机制使我们能够将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发生竞争的过程。这有时在想法上被简化 反复的上皮损伤导致干细胞衰竭，从而创造一个无情的促纤维化环境。但 肺具有弹性，具有多个空间上不同的祖细胞，其识别和整合功能 仍然知之甚少，特别是在 IPF 患者中。这种范式还忽视了潜在的关键问题 促纤维化间充质细胞在驱动上皮进一步损失中的贡献。 IPF 中的 II 型细胞 肺移植时肺的体积小于正常肺的 15%。该计划将重点 进一步阐明小鼠和人类中驻留上皮干细胞/祖细胞的再生潜力 肺泡完整性。与此同时，活化的间充质细胞导致功能障碍和 这些上皮祖细胞的损失将被确定。我们计划利用成纤维细胞特异性 TGFb1 抑制作用 研究其对动物模型和 IPF 患者祖细胞的影响，例如通过单细胞 RNA- 来自未经治疗和 EGCG 治疗患者的组织序列。我们设想未来基于小分子图像 筛选以确定可改善培养的上皮/成纤维细胞类器官中 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整合到一个中心主题中， 多维方法应该改变我们对肺再生和纤维发生的看法以及我们如何看待肺再生和纤维发生 治疗患有持续纤维化的患者。