Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction

端粒功能障碍是慢性同种异体肺移植功能障碍的原因

• 批准号: 10397632
• 负责人: JOHN GREENLAND
• 金额: $ 29.96万
• 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: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397632
• 关键词: Affect; Age; Allografting; Award; Biopsy; Biopsy Specimen; Bronchiolitis; Cell Aging; Cells; Cessation of life; Characteristics; Chromosomes; Chronic; Clinical; Closure by clamp; Cohort Studies; Cox Models; Cox Proportional Hazards Models; Data; Development; Disease; Donor Selection; Donor person; Enrollment; Epithelial; Epithelial Cells; Failure; Fluorescent in Situ Hybridization; Functional disorder; Genetic; Genetic Risk; Genetic Variation; Genotype; Hand; Hilar; Human; Human Chromosomes; IL2RG gene; Immune; Immune response; Immunofluorescence Immunologic; Immunosuppression; Impairment; Inflammation; Injury; Intervention; Investigation; Isogenic transplantation; Label; Lead; Length; Link; Longitudinal cohort; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Measures; Mediating; Molecular; Mus; Nucleoproteins; Organ; Outcome; Pathogenesis; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Play; Proliferating; Pulmonary Surfactant-Associated Protein C; Rehabilitation therapy; Reperfusion Injury; Risk; Risk Assessment; Risk Factors; Role; Sampling; Secondary to; Solid; Telomere Shortening; Testing; Therapeutic Intervention; Time; Tissues; Transplant Recipients; Transplantation; alveolar epithelium; cohort; constriction; epithelial stem cell; fibrotic lung disease; genetic variant; graft dysfunction; idiopathic pulmonary fibrosis; improved; improved outcome; innovation; loss of function; lung allograft; lung injury; mouse model; novel; novel diagnostics; peripheral blood; post-transplant; prospective; response; stem cells; telomere

Project Summary Lung transplantation is a potentially lifesaving option for patients with end-stage lung diseases, such as idiopathic pulmonary fibrosis (IPF). However, the median survival following lung transplantation is less than six years, limited primarily by chronic lung allograft dysfunction (CLAD). Emerging data suggest that dysfunction of telomeres, the nucleoprotein caps that protect chromosomes during cellular replication, can result in IPF. It is unknown whether telomere dysfunction also plays a role in CLAD. Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure. Our preliminary data show that shorter telomeres in peripheral blood of lung allograft donors predict decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway progenitor cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans, progenitor cells such as type II alveolar epithelial cells (AEC2) can proliferate and differentiate to restore epithelial integrity following injury. Thus, AEC2 failure, driven by telomere dysfunction, could lead to denuded alveolar epithelium that is replaced by fibrotic tissue. With the support of this award, we will test the innovative hypothesis that telomere dysfunction is a molecular driver of CLAD. In Study Aim 1, we will evaluate the associations between telomere genetic variants and CLAD in a large, established, multi-center cohort of lung transplant recipients. Common genetic variants resulting in short telomeres will be sequenced, and telomere length will be determined by quantitative PCR. We will use adjusted Cox proportional hazards models to evaluate the links between donor telomere length or genotype and CLAD-free survival time. These findings will help distinguish the contributions of innate and acquired telomere dysfunction to poor post-transplant outcomes. Study Aim 2 will test the association between short allograft AEC2 telomeres and CLAD-free survival in a longitudinal cohort. AEC2 telomere length will be determined by fluorescence-in situ hybridization with a telomere-specific probe (Telo- FISH) on transbronchial biopsy tissues co-labeled with the AEC2 maker, surfactant protein C. We will test the association between AEC2 telomere length within the first 60 days post-transplant and CLAD-free survival using adjusted Cox models. This aim will directly assess the link between early AEC2 telomere dysfunction and CLAD. In Study Aim 3, we will determine whether transplant-associated lung injury and lymphocytic inflammation are associated with time to CLAD, using a novel murine model of telomere-mediated CLAD pathology. Overall, this proposed investigation has the potential to challenge our conceptual understanding of CLAD and inform cutting edge therapeutic interventions. Establishing telomere dysfunction as a molecular driver of CLAD would be new paradigm, potentially transforming clinical approaches and thus improving outcomes for patients with end-stage lung disease.

项目摘要 对于终末期肺部疾病的患者，肺移植是一种潜在的救生选择，例如 特发性肺纤维化（IPF）。但是，肺移植后的中位生存率小于 六年，主要受慢性肺同种异体移植功能障碍（CLAD）限制。新兴数据表明 端粒功能障碍，端粒，保护细胞复制过程中保护染色体的核蛋白帽可以 结果IPF。未知端粒功能障碍是否也在外壳中起作用。是这样， 需要移植的相同病理生理学也可能是其失败的基础。我们的初步数据 表明肺同种异体移植供体的外周血中的端粒较短，预测肺的存活率降低 同种异体移植者。我们还发现，气道祖细胞中的端粒功能障碍足以 在实验性鼠模型中诱导外壳的病理标志。在人类中，祖细胞这样 由于II型肺泡上皮细胞（AEC2）可以增殖并区分以恢复上皮完整性。 受伤。因此，由端粒功能障碍驱动的AEC2故障可能​​导致裸露的肺泡上皮 被纤维化组织取代。在该奖项的支持下，我们将检验端粒的创新假设 功能障碍是外壳的分子驱动器。在研究目标1中，我们将评估端粒之间的关联 遗传变异和甲壳动物中的大型，多中心的肺移植受者队列。常见的 将测序导致短端粒的遗传变异，端粒长度将由 定量PCR。我们将使用调整后的COX比例危害模型来评估捐助者之间的联系 端粒长度或基因型和无外壳生存时间。这些发现将有助于区分贡献 对较差的移植后结局的先天和获得的端粒功能障碍。研究目标2将测试 在纵向队列中，简短的同种异体AEC2端粒和无外壳生存之间的关联。 AEC2 端粒长度将通过与端粒特异性探针（telo- FISH）在与AEC2制造剂表面活性剂蛋白的经支气管活检组织上 移植后的前60天内AEC2端粒长度与无外壳生存之间的关联 使用调整后的COX型号。该目标将直接评估早期AEC2端粒功能障碍之间的联系 和外壳。在研究目标3中，我们将确定是否与移植相关的肺损伤和淋巴细胞 使用端粒介导的新型鼠模型，炎症与甲壳的时间有关 病理。总体而言，这项提出的调查有可能挑战我们的概念理解 外壳和尖端治疗干预措施的信息。建立端粒功能障碍作为分子 外壳的驱动程序将是新的范式，有可能改变临床方法，从而改善 末期肺部疾病患者的结局。