Lung Allograft Stem Cell Regeneration and Immune Destruction

同种异体肺干细胞再生和免疫破坏

• 批准号: 10545033
• 负责人: Thomas J Lynch
• 金额: $ 8.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545033
• 关键词: Address; Adopted; Allografting; Animal Model; Antigens; Autoantigens; Autoimmune; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Bypass; Cause of Death; Cell Compartmentation; Cell Lineage; Cell surface; Cells; Chronic; Data; Development; Disease; Disease Progression; Distal; Duct (organ) structure; Ductal Epithelial Cell; Ectopic Expression; Epithelial Cells; Ferrets; Fibrosis; Foundations; Functional disorder; Gland; Goals; Health; Human; Immune; Immune Targeting; Immune mediated destruction; Immune response; Immune system; Impairment; Injury; K-Series Research Career Programs; Knowledge; Left; Lung; Lung Transplantation; Lung diseases; Lymphoid Follicle; Modeling; Morbidity - disease rate; Multipotent Stem Cells; Myoepithelial cell; Natural regeneration; Pathology; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiology; Process; Property; Proteins; Publishing; Reaction; Regenerative Medicine; Research; Reserve Stem Cell; Rodent Model; Role; Signal Transduction; Stress; Submucosa; Surface; Testing; Transgenic Organisms; Transplantation; Work; activation-induced cytidine deaminase; airway epithelium; airway regeneration; epithelial stem cell; epithelium regeneration; experience; improved; in vitro Assay; in vivo; injured airway; innovation; insight; lung allograft; novel; pressure; prevent; progenitor; pulmonary function; pulmonary function decline; reconstitution; regeneration function; regenerative; resilience; response; severe injury; stem cell niche; stem cell self renewal; stem cell therapy; stem cells; transplant model

PROJECT SUMMARY: End-stage lung disease is the third leading cause of death worldwide. Lung transplantation is often the only option for patients with advanced lung disease, yet 50% of recipients die within five years due to the development of chronic lung allograft dysfunction (CLAD). This project seeks to examine the basis for the loss of region-specific stem cells and impaired airway regeneration, with a long-term goal of improving cell-based regenerative medicine approaches. We will make use of innovative transgenic ferret models in our well-established orthotopic lung transplantation model. We will investigate the role of glandular myoepithelial cells (MECs) in renewing submucosal gland (SMG) cells and generating abnormal surface basal stem cells (BSCs) in CLAD. We hypothesize that sustained regenerative pressures drive MECs to exit their SMG stem cell niche to reconstitute surface BSCs with abnormal lineage properties that promote an immune response. Additionally, this project will determine the regenerative function of KRT7+ glandular duct cells (DCs) during the progression of CLAD. We hypothesize that the gland duct is a maturation point for MEC stem cells to adopt a surface BSCs phenotype that is bypassed under sustained regenerative stresses in CLAD. Finally, we will determine the relationship of antigen-experienced B-cells in promoting alloimmune and autoimmune reactions against airway stem cells to drive CLAD. We hypothesize that prolonged regeneration of surface BSCs by reserve MEC stem cells leads to the retention of MEC proteins on the airway surface. This ectopic expression of self-antigens promotes an autoimmune response against the SMG stem cells niche. Currently, end-stage lung disease is a significant cause of morbidity. However, we expect that by clarifying the processes that deplete stem cells in transplanted lungs, we will improve the likelihood of developing long-term objectives of developing effective stem cell therapies to sustain lung function and resilience to prevent CLAD.

项目摘要：末期肺病是全球死亡的第三大主要原因。肺 移植通常是患有晚期肺部疾病的患者的唯一选择，但有50％的接受者死亡 由于慢性同种异体移植功能障碍（CLAD）的发展五年。这个项目试图检查 损失区域特异性干细胞和气道再生的基础，其长期目标的 改善基于细胞的再生医学方法。我们将利用创新的转基因雪貂 我们建立的原位肺移植模型中的模型。我们将研究腺的作用 续签粘膜腺（SMG）细胞中的肌上皮细胞（MEC），并产生异常表面基础 clad中的干细胞（BSC）。我们假设持续的再生压力驱动MEC退出SMG 干细胞生态位以重建具有异常谱系特性的表面BSC，以促进免疫反应。 此外，该项目将确定KRT7+腺管细胞（DC）的再生功能 外壳的进展。我们假设腺管是MEC干细胞采用A的成熟点 表面BSC表型在甲壳中持续的再生应力下绕过。最后，我们会的 确定抗原经验的B细胞在促进同种免疫和自身免疫反应中的关系 针对气道干细胞驱动外壳。我们假设通过 储备MEC干细胞导致MEC蛋白在气道表面上保留。这种异位表达 自我抗原的促进了针对SMG干细胞生态位的自身免疫反应。目前，末期肺 疾病是发病率的重要原因。但是，我们希望通过澄清耗尽茎的过程 移植肺中的细胞，我们将提高发展长期目标的可能性 有效的干细胞疗法维持肺功能和弹性以防止外壳。