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 肺移植是终末期肺部疾病患者的一种潜在救生选择，例如 特发性肺纤维化（IPF）。然而，肺移植后的中位存活率低于 6年，主要受限于慢性肺移植物功能障碍（CLAD）。新出现的数据表明， 端粒（在细胞复制过程中保护染色体的核蛋白帽）的功能障碍， 导致IPF。尚不清楚端粒功能障碍是否也在CLAD中起作用。如果是这样， 需要移植的病理生理学也可能是其失败的原因。我们的初步数据 表明肺移植供体外周血中较短的端粒预示着肺移植供体存活率降低， 同种异体移植受者。我们还发现，气道祖细胞中的端粒功能障碍足以 在实验鼠模型中诱导CLAD的病理标志。在人类中，祖细胞， 因为II型肺泡上皮细胞（AEC 2）可以增殖和分化以恢复上皮完整性， 损伤因此，由端粒功能障碍驱动的AEC 2失败可能导致裸露的肺泡上皮细胞， 被纤维化组织取代。在这个奖项的支持下，我们将测试创新的假设，即端粒 功能障碍是CLAD的分子驱动因素。在研究目标1中，我们将评估端粒之间的关联 遗传变异和CLAD在一个大的，建立的，多中心队列的肺移植受体。共同 将对导致短端粒的遗传变异进行测序，并通过以下方法确定端粒长度： 定量PCR。我们将使用调整后的考克斯比例风险模型来评估捐赠者之间的联系。 端粒长度或基因型和无CLAD生存时间。这些发现将有助于区分 先天性和后天性端粒功能障碍与移植后不良结局的关系。研究目标2将测试 在纵向队列中，短同种异体移植物AEC 2端粒与无CLAD生存率之间的相关性。AEC2 端粒长度将通过用端粒特异性探针（Telo- FISH）对经支气管活检组织进行标记。我们将测试 移植后前60天内AEC 2端粒长度与无CLAD生存率之间的关系 使用调整后的考克斯模型。这一目标将直接评估早期AEC 2端粒功能障碍与 和CLAD。在研究目标3中，我们将确定移植相关的肺损伤和淋巴细胞是否 使用端粒介导CLAD的新型鼠模型，炎症与CLAD的时间相关 病理总的来说，这项拟议的调查有可能挑战我们的概念理解 并告知最先进的治疗干预措施。将端粒功能障碍作为一种分子机制 CLAD的驱动因素将是新的范例，可能会改变临床方法，从而改善 终末期肺病患者的预后。