Therapeutic Targeting of PTPN13 in Idiopathic Pulmonary Fibrosis

PTPN13 在特发性肺纤维化中的治疗靶向

• 批准号: 9142965
• 负责人: David W. Riches
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142965
• 关键词: Address; Adoptive Transfer; Adult Respiratory Distress Syndrome; Aging; Alveolar; Alveolar wall; American; Apoptosis; Architecture; Binding; Bleomycin; Blood capillaries; Breathing; C-terminal; CASP8 gene; CD95 Antigens; Cessation of life; Cicatrix; Data; Development; Diagnosis; Disease; Dust; Event; Exposure to; Extracellular Matrix; FDA approved; Fas-associated phosphatase-1; Fibroblasts; Fibrosis; Gases; General Population; Generic Drugs; Genetic; Goals; Hamman-Rich syndrome; Healthcare; Human; Immunodeficient Mouse; Impairment; Induction of Apoptosis; Inhalation Burns; Innovative Therapy; Lung; Lung diseases; Mediating; Mediator of activation protein; Military Personnel; Modeling; Mus; Myofibroblast; Patients; Persons; Pharmaceutical Preparations; Poison; Process; Protein Tyrosine Phosphatase; Pulmonary Fibrosis; Quality of life; Recruitment Activity; Resistance; Resistance development; Resolution; Respiratory Failure; Risk; Risk Factors; Role; Series; Signal Transduction; Signaling Molecule; Silicon Dioxide; Smoke; Structure of parenchyma of lung; Testing; Therapeutic; Translating; Veterans; Work; Wound Healing; Xenograft Model; analytical method; base; capillary; cigarette smoking; cigarette smoking; design; drug testing; effective therapy; high throughput screening; humanized mouse; improved; in vivo; inhibitor/antagonist; injured; innovation; interest; male; mimetics; mortality; mouse model; new therapeutic target; novel; outcome forecast; pollutant; premature; prevent; protein tyrosine phosphatase BL; public health relevance; repaired; small molecule; small molecule inhibitor; small molecule libraries; therapeutic development; therapeutic target; tool; translational impact

 DESCRIPTION (provided by applicant): Project summary Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that compromises gas exchange in the alveoli. The median survival following diagnosis is approximately 3 years and there are few effective therapies. Although the specific causes of IPF are unknown, inhalation of dust, cigarette smoke and toxic chemicals are known risk factors for developing the disease, which most commonly develops in males as they enter their 60s and 70s. In view of these risk factors, the Department of Veterans Affairs has become increasingly concerned about the potential for previously deployed US Veterans to develop IPF. One of the cardinal features of IPF is the accumulation and persistence of fibroblasts in the alveoli and alveolar septa. Fibroblasts participating in homeostatic repair processes undergo apoptosis at the completion of the repair process. In contrast, fibroblasts from the lungs of IPF patients are resistant to apoptosis. Our lab has had a long-standing interest in fibroblast apoptosis and the role of the death receptor Fas in this process. This proposal is focused on the mechanisms that cause the resistance of lung fibroblasts from IPF patients to apoptosis. In preliminary studies, we have identified the protein tyrosine phosphatase, PTPN13 (also called PTP-BL in mice), as a central mediator of the resistance of human lung fibroblasts to Fas-induced apoptosis. PTPN13 inhibits apoptosis by binding to the C-terminal cytoplasmic region of Fas, thereby preventing recruitment of the required death signaling molecules FADD and caspase-8. Our preliminary studies suggest that PTPN13 is a therapeutic target, which, when antagonized, will overcome the resistance of fibrotic lung fibroblasts to Fas-induced apoptosis. We hypothesize that interfering with PTPN13 function will restore the ability of fibrotic lung fibroblasts to undergo Fas-induced apoptosis, leading to a progressive reduction in lung fibroblast numbers a resolution of established fibrosis. This hypothesis will be tested with 3 specific aims. In aim 1, we propose investigating the consequence of genetic deficiency of PTP-BL (the murine orthologue of human PTPN13) on resolving and non-resolving models of pulmonary fibrosis in mice. Using specific analytic methods developed for this proposal, including fibroblast lineage tracing, we propose investigating the effect of PTP-BL deficiency on lung fibroblast numbers and fibrosis resolution. Next, while genetic deficiency of PTP-BL is a useful experimental tool, our goal is to rapidly translate our work into humans. Consequently we have developed a therapeutic pipeline to identify small molecule inhibitors of the interaction between Fas and PTPN13. Using a high throughput assay to screen 20,831 small molecules and FDA-approved drugs, we have identified 3 molecules that behave as mimetics of the Fas sequence responsible for its interaction with PTPN13. These small molecules competitively inhibit the interaction between Fas and PTPN13 and sensitize lung fibroblasts to Fas-induced apoptosis. Furthermore, one of the molecules is an FDA-approved drug, shortening the pipeline for therapeutic development. In aim 2, we propose testing this drug for its ability to enable fibroblas apoptosis in a humanized mouse model and resolve established pulmonary fibrosis. Lastly, in aim 3 we proposed investigating the mechanisms controlling PTPN13 expression. Our preliminary studies suggest that lung "stiffness" is an important factor in this event. Collectivel, the proposed studies should innovative understanding of fibroblast persistence in pulmonary fibrosis, address a novel therapeutic target (PTPN13) and provide proof-of-concept data about a repurposed FDA-approved drug that by antagonizing PTPN13 function is predicted to augment lung fibroblast apoptosis and resolve established pulmonary fibrosis.

 描述（由申请人提供）： 项目摘要 特发性肺纤维化 (IPF) 是一种致命的纤维化肺部疾病，会损害肺泡中的气体交换。诊断后的中位生存期约为 3 年，且有效的治疗方法很少。尽管 IPF 的具体原因尚不清楚，但吸入灰尘、香烟烟雾和有毒化学物质是已知的导致这种疾病的危险因素，这种疾病最常见于 60 多岁和 70 多岁的男性。鉴于这些风险因素，退伍军人事务部越来越担心先前部署的美国退伍军人患上 IPF 的可能性。 IPF 的主要特征之一是成纤维细胞在肺泡和肺泡间隔中积聚和持续存在。参与稳态修复过程的成纤维细胞在修复过程完成后会发生细胞凋亡。相比之下，IPF 患者肺部的成纤维细胞对细胞凋亡具有抵抗力。我们的实验室长期以来对成纤维细胞凋亡以及死亡受体 Fas 在此过程中的作用感兴趣。该提案重点研究导致IPF患者肺成纤维细胞抵抗细胞凋亡的机制。在初步研究中，我们发现蛋白质酪氨酸磷酸酶 PTPN13（在小鼠中也称为 PTP-BL）是人肺成纤维细胞抵抗 Fas 诱导的细胞凋亡的核心介质。 PTPN13 通过与 Fas C 端胞质区域结合来抑制细胞凋亡，从而阻止所需死亡信号分子 FADD 和 caspase-8 的募集。我们的初步研究表明，PTPN13 是一个治疗靶点，当被拮抗时，将克服纤维化肺成纤维细胞对 Fas 诱导的细胞凋亡的抵抗。我们假设干扰 PTPN13 功能将恢复纤维化肺成纤维细胞经历 Fas 诱导的细胞凋亡的能力，导致肺成纤维细胞数量逐渐减少，从而解决已确定的纤维化。该假设将通过 3 个具体目标进行检验。在目标 1 中，我们建议研究 PTP-BL（人 PTPN13 的鼠类直系同源物）遗传缺陷对小鼠肺纤维化缓解和非缓解模型的影响。使用为本提案开发的特定分析方法（包括成纤维细胞谱系追踪），我们建议研究 PTP-BL 缺陷对肺成纤维细胞数量和纤维化消退的影响。接下来，虽然 PTP-BL 的遗传缺陷是一种有用的实验工具，但我们的目标是快速将我们的工作转化为人类。因此，我们开发了一种治疗管道来识别 Fas 和 PTPN13 之间相互作用的小分子抑制剂。使用高通量测定筛选 20,831 个小分子和 FDA 批准的药物，我们鉴定了 3 个分子，它们充当负责与 PTPN13 相互作用的 Fas 序列的模拟物。这些小分子竞争性抑制 Fas 和 PTPN13 之间的相互作用，并使肺成纤维细胞对 Fas 诱导的细胞凋亡敏感。此外，其中一种分子是 FDA 批准的药物，缩短了治疗开发的流程。在目标 2 中，我们建议测试该药物在人源化小鼠模型中促进成纤维细胞凋亡并解决已形成的肺纤维化的能力。最后，在目标 3 中，我们建议研究控制 PTPN13 表达的机制。我们的初步研究表明，肺部“僵硬”是这一事件的一个重要因素。总的来说，拟议的研究应该对肺纤维化中成纤维细胞的持久性有创新的理解，解决一个新的治疗靶点（PTPN13），并提供有关 FDA 批准的药物的概念验证数据，该药物通过拮抗 PTPN13 功能，预计会增加肺成纤维细胞凋亡并解决已形成的肺纤维化。