Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction

加速衰老是慢性同种异体肺移植功能障碍的原因

• 批准号: 10662220
• 负责人: JOHN GREENLAND
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR 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: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662220
• 关键词: Acceleration; Acute Lung Injury; Affect; Age; Aging; Allografting; Award; Biological Markers; Biopsy; Biopsy Specimen; Bronchiolitis; Cell Aging; Cell Differentiation process; Cells; Cessation of life; Characteristics; Chromosomes; Chronic; Clinical; Cohort Studies; Cox Models; Cox Proportional Hazards Models; DNA Methylation; DNA Repair; Data; Development; Diagnostic; Disease; Donor Selection; Donor person; Enrollment; Epigenetic Process; Epithelial Cells; Epithelium; Failure; Fibrosis; Fluorescent in Situ Hybridization; Functional disorder; Genes; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genotype; Hand; Human; Immune; Immune response; Immunofluorescence Immunologic; Immunosuppression; Impairment; In Vitro; Inflammation; Injury; Intervention; Investigation; Length; Life; Linear Models; Link; Longitudinal cohort; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Measurement; Measures; Mediating; Methylation; Molecular; Mus; Neurodegenerative Disorders; Nucleoproteins; Organ; Outcome; Pathogenesis; Pathologic; Pathway interactions; Perioperative; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Plasma Cells; Prevalence; Pulmonary Inflammation; RNA; Rapid diagnostics; Rehabilitation therapy; Risk Assessment; Risk Factors; Role; Sampling; Shapes; Solid; Telomere Shortening; Testing; Therapeutic Intervention; Time; Tissues; Transplant Recipients; Transplantation; Veterans; airway epithelium; airway regeneration; bisulfite sequencing; cell free DNA; cell injury; cell type; cohort; digital; epithelial stem cell; fibrotic lung disease; genetic variant; graft dysfunction; idiopathic pulmonary fibrosis; improved outcome; injured airway; innovation; insight; lung allograft; methylation pattern; mortality risk; mouse model; next generation; novel; novel marker; peripheral blood; post-transplant; prospective; recruit; response; stem cell proliferation; stem cells; technology development; telomere; transcriptomics

Lung transplantation is a lifesaving option for veterans with end-stage lung diseases, in particular idiopathic pulmonary fibrosis (IPF). Veterans appear to be disproportionately affected by IPF, a disease that has been described as early aging of the lung. IPF is usually fatal unless the lungs are replaced by transplant. Even following lung transplantation median survival is less than six years, limited primarily by chronic lung allograft dysfunction (CLAD). Emerging data suggest that telomeres, the nucleoprotein caps that protect chromosomes during cellular replication, are involved in IPF, but it is unknown whether telomeres also play a role in CLAD. Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure. Our own preliminary data show that impaired telomeres in peripheral blood of lung allograft donors are linked to decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway stem cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans, airway progenitor cells proliferate and differentiate to restore airway epithelial integrity following injury. Thus, telomere dysfunction could lead to airway epithelial cell progenitor failure, resulting in denuded airways that are subsequently replaced by fibrotic tissue. With the support of this Merit Award, we will test the innovative hypothesis that telomere dysfunction leads to 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 from donor cells, 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 post-transplant survival time. Novel genotypic associations with telomere dysfunction will be validated in vitro. 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 epithelial cell telomeres and CLAD-free survival in a longitudinal cohort. Epithelial telomere lengths will be determined by fluorescence-in situ hybridization with a telomere-specific probe (Telo-FISH) on endobronchial and transbronchial biopsy tissues. We will test the association between telomere length and CLAD-free survival using adjusted Cox models and examine transcriptomic sequelae of telomere dysfunction. In Study Aim 3, we will determine whether airway epithelial cell injury is associated with allograft telomere shortening and epigenetic aging in a prospectively enrolled cohort of lung transplant recipients. Early allograft injury will be assessed clinically by the presence of primary graft dysfunction (PGD). We also quantify allograft epithelial cell injury from recipient plasma cell-free DNA using next-generation bisulfite sequencing to enumerate donor-specific polymorphisms and cell-type specific DNA methylation patterns. We will test for associations between PGD and cell-free DNA measurements of allograft injury with telomere-based and epigenetic metrics of allograft aging using adjusted linear models. These findings will shed light on the longstanding question of how acute lung injury and inflammation develop into chronic fibrosis. Further, these studies could establish that CLAD is an evoked phenotype in which telomere dysfunction leads to impaired epithelial responses to chronic transplant-associated airway injury. Overall, this proposed investigation has the potential to reshape our conceptual understanding of CLAD and lead to novel biomarkers that could inform cutting edge therapeutic interventions. This would be new paradigm, potentially transforming our approach CLAD and thus improving outcomes for veterans with end- stage lung disease.

对于患有终末期肺部疾病，特别是特发性肺部疾病的退伍军人来说，肺移植是一种挽救生命的选择 肺纤维化(IPF)。退伍军人似乎不成比例地受到IPF的影响，这种疾病已经 被描述为肺的早期老化。除非通过移植替代肺部，否则IPF通常是致命的。连 肺移植后的中位生存期不到6年，主要受慢性同种异体肺移植的限制。 功能障碍(外衣)。新出现的数据表明，端粒，保护染色体的核蛋白帽 在细胞复制过程中，都参与了IPF，但端粒是否也在包膜中发挥作用尚不清楚。 如果是这样的话，导致移植的病理生理学也可能是它失败的原因。 我们自己的初步数据显示，肺移植供者外周血中受损的端粒与 导致同种异体肺移植患者存活率下降。我们还发现，气道干中的端粒功能障碍 细胞足以在实验小鼠模型中诱导出CLAD的病理特征。在人类身上， 损伤后，呼吸道祖细胞增殖和分化以恢复呼吸道上皮细胞的完整性。因此， 端粒功能障碍可能导致呼吸道上皮细胞前体细胞衰竭，导致裸露的呼吸道 随后被纤维组织取代。在此次功勋奖的支持下，我们将测试创新的 端粒功能障碍导致包衣的假说。在研究目标1中，我们将评估这些关联 在大型已建立的多中心肺移植队列中端粒基因变异体和包膜之间 收件人。将从供体细胞中对导致端粒缩短的常见遗传变异进行测序，并 端粒长度将通过定量聚合酶链式反应测定。我们将使用调整后的COX比例风险 评估供体端粒长度或基因与移植后存活时间之间关系的模型。 新的基因型别与端粒功能障碍的关系将在体外得到验证。这些发现将会有所帮助 区分先天和后天端粒功能障碍对移植后不良结果的影响。 研究目标2将测试短的同种异体移植上皮细胞端粒与无包膜存活的关系。 在纵向队列中。上皮端粒长度将通过荧光原位杂交来确定 用端粒特异性探针(TELO-FISH)对经支气管镜活检组织和经支气管镜活检组织进行检测。我们将测试 端粒长度与无包膜生存期的关系 端粒功能障碍的转录性后遗症。在研究目标3中，我们将确定呼吸道上皮细胞 一项前瞻性研究表明细胞损伤与同种异体移植的端粒缩短和表观遗传学老化有关 肺移植受者的队列。早期同种异体移植物损伤将通过临床评估是否存在原发 移植物功能障碍(PGD)。我们还量化了来自受体无浆细胞DNA的同种异体移植上皮细胞损伤 使用下一代亚硫酸氢盐测序来计数供体特异性多态和细胞类型特异性 DNA甲基化模式。我们将测试PGD和无细胞DNA测量之间的关联 基于端粒和表观遗传学指标的同种移植物损伤：使用调整的线性模型。 这些发现将阐明一个长期存在的问题，即急性肺损伤和炎症是如何发展的 变成慢性纤维化。此外，这些研究可以确定CLAD是一种诱发的表型，其中 端粒功能障碍导致上皮细胞对慢性移植相关的呼吸道损伤的反应受损。 总体而言，这项拟议的调查有可能重塑我们对穿着和 导致新的生物标记物，可以为尖端治疗干预提供信息。这将是新的 范式，潜在地改变了我们的方法，从而改善了退伍军人的结局 肺部疾病的阶段。

项目成果

Different involvement of promoter methylation in the expression of organic cation/carnitine transporter 2 (OCTN2) in cancer cell lines.

启动子甲基化对癌细胞系中有机阳离子/肉碱转运蛋白 2 (OCTN2) 表达的不同参与

• DOI: 10.1371/journal.pone.0076474
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Qu Q;Qu J;Zhan M;Wu LX;Zhang YW;Lou XY;Fu LJ;Zhou HH
• 通讯作者: Zhou HH

Phenomics of Vascular Disease: The Systematic Approach to the Combination Therapy.

• DOI: 10.2174/1570161112666141014144829
• 发表时间: 2015
• 期刊: Current vascular pharmacology
• 影响因子: 4.5
• 作者: Han Y;Li L;Zhang Y;Yuan H;Ye L;Zhao J;Duan DD
• 通讯作者: Duan DD

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

慢性肺同种异体移植功能障碍小气道揭示了淋巴细胞炎症基因特征。

• DOI: 10.1111/ajt.16293
• 发表时间: 2021-01
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Dugger DT;Fung M;Hays SR;Singer JP;Kleinhenz ME;Leard LE;Golden JA;Shah RJ;Lee JS;Deiter F;Greenland NY;Jones KD;Langelier CR;Greenland JR
• 通讯作者: Greenland JR

Theseus and the search for an antibody-mediated rejection molecular state in lung transplant biopsies.

忒修斯和在肺移植活检中寻找抗体介导的排斥分子状态。

• DOI: 10.1016/j.ajt.2023.08.003
• 发表时间: 2023
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Calabrese,DanielR;Greenland,JohnR
• 通讯作者: Greenland,JohnR

NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.

• DOI: 10.1172/jci.insight.164603
• 发表时间: 2022-12-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Calabrese, Daniel R.;Tsao, Tasha;Magnen, Melia;Valet, Colin;Gao, Ying;Mallavia, Benat;Tian, Jennifer J.;Aminian, Emily A.;Wang, Kristin M.;Shemesh, Avishai;Punzalan, Elman B.;Sarma, Aartik;Calfee, Carolyn S.;Christenson, Stephanie A.;Langelier, Charles R.;Hays, Steven R.;Golden, Jeffrey A.;Leard, Lorriana E.;Kleinhenz, Mary Ellen;Kolaitis, Nicholas A.;Shah, Rupal;Venado, Aida;Lanier, Lewis L.;Greenland, John R.;Sayah, David M.;Ardehali, Abbas;Kukreja, Jasleen;Weigt, S. Samuel;Belperio, John A.;Singer, Jonathan P.;Looney, Mark R.
• 通讯作者: Looney, Mark R.