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 Unpublished data show reversal of a core set of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy.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 本研究的目的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，以提供新的治疗干预肺纤维化，一个没有疾病的过程， 改良疗法该计划由最近资助的RO 1锚定，以进一步阐明 L0 XL 2和TGFR 1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 将测试其中之一，表没食子儿茶素没食子酸酯，在一个证明原则的临床试验。未公布的数据显示， 在诊断性肺活检前两周给予EGCG的IPF患者的促纤维化组织生物标志物。的 R35机制使我们能够将我们减弱纤维化的能力与更广泛的缺陷性肝纤维化问题相结合。 IPF中的上皮再生，与纤维形成竞争的过程。这有时被简化为 反复的上皮损伤导致干细胞衰竭，从而创造出无情的促纤维化环境。但 肺具有多个空间上不同祖细胞的弹性，所述祖细胞的识别和整合功能 对这一点的了解仍然很少，特别是在IPF患者中。这种模式也忽略了潜在的关键 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 在肺移植时，肺中存在的量小于正常肺中存在的量的15%。该计划将重点 进一步阐明小鼠和人类中常驻上皮干细胞/祖细胞再生的潜力 肺泡完整性与此同时，激活的间充质细胞导致功能障碍和 将定义这些上皮祖细胞的损失。我们计划利用成纤维细胞特异性TGF β 1抑制， 研究其对动物模型和IPF患者中祖细胞的影响，例如通过单细胞RNA- 来自未治疗和EGCG治疗的患者的组织的序列。我们设想未来的小分子图像为基础的 筛选以鉴定在培养的上皮/成纤维细胞类器官中改善II型细胞健康的试剂。总体 R35计划使我们有机会将所有这些方向整合到一个集中的主题， 多维度的方法，应该改变我们如何看待肺再生和纤维化， 治疗顽固性纤维化患者