Lung Allograft Stem Cell Regeneration and Immune Destruction

同种异体肺干细胞再生和免疫破坏

基本信息

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
项目类别：
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

项目摘要

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：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% 的受者在体内死亡由于慢性肺同种异体移植功能障碍（CLAD）的发展，已经五年了。该项目旨在审查区域特异性干细胞丢失和气道再生受损的基础，长期目标是改进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完善的原位肺移植模型中的模型。我们将研究腺体的作用肌上皮细胞 (MEC) 更新粘膜下腺 (SMG) 细胞并产生异常表面基底细胞 CLAD 中的干细胞 (BSC)。我们假设持续的再生压力驱使 MEC 退出 SMG 干细胞生态位重建具有异常谱系特性的表面BSC，从而促进免疫反应。此外，该项目将确定 KRT7+ 腺管细胞 (DC) 在 CLAD 的进展。我们假设腺管是 MEC 干细胞采用的成熟点 CLAD 中持续再生应力下绕过的表面 BSC 表型。最后，我们将确定经历抗原的 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 BSC 的再生时间储备 MEC 干细胞导致 MEC 蛋白保留在气道表面。这种异位表达自身抗原促进针对 SMG 干细胞生态位的自身免疫反应。目前，终末期肺疾病是发病的重要原因。然而，我们希望通过澄清消耗茎的过程移植肺中的细胞，我们将提高制定长期发展目标的可能性有效的干细胞疗法可维持肺功能和恢复能力，以预防 CLAD。