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: 10370655
• 负责人: Thomas J Lynch
• 金额: $ 8.99万
• 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/10370655
• 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; Surface; Testing; Transgenic Organisms; Transplant Recipients; Transplantation; Work; activation-induced cytidine deaminase; airway epithelium; airway regeneration; base; 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.

终末期肺病是全球第三大死亡原因。肺 移植通常是晚期肺病患者的唯一选择，但50%的接受者在手术后10分钟内死亡。 由于慢性肺移植物功能障碍（CLAD）的发展，该项目旨在研究 区域特异性干细胞丢失和气道再生受损的基础，长期目标是 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 在我们完善的原位肺移植模型中。我们将研究腺体的作用， 肌上皮细胞（MEC）更新粘膜下腺（SMG）细胞，并产生异常的表面基底膜， 干细胞（BSC）在CLAD中的作用。我们假设持续的再生压力驱动MEC退出SMG 干细胞小生境以重建具有促进免疫应答的异常谱系特性的表面BSC。 此外，该项目将确定KRT7+腺管细胞（DC）在移植过程中的再生功能。 CLAD的进展。我们假设腺管是MEC干细胞的成熟点， 在CLAD中，在持续的再生应激下绕过表面BSC表型。最后我们将 确定抗原感受B细胞在促进同种免疫和自身免疫反应中的关系 对抗气道干细胞来驱动CLAD。我们假设，通过延长表面BSCs的再生时间， 保留MEC干细胞导致MEC蛋白质保留在气道表面上。这种异位表达 自身抗原的增加促进了针对SMG干细胞小生境的自身免疫应答。目前，晚期肺 疾病是发病的一个重要原因。然而，我们希望通过澄清消耗stem的过程， 细胞移植肺，我们将提高发展的长期目标的可能性， 有效的干细胞疗法，以维持肺功能和韧性，以防止CLAD。