Epithelial Stem Cells in Lung Transplantation

上皮干细胞在肺移植中的应用

• 批准号: 8352868
• 负责人: Kalpaj Rajnikant Parekh
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352868
• 关键词: Acute; Address; Affect; Allografting; Anatomic Sites; Animal Model; Animals; Biological Assay; Biology; Biopsy Specimen; Bronchiolitis; Bronchiolitis Obliterans; Calcitonin Gene-Related Peptide; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Cholecystokinin; Chronic; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Denervation; Deoxyuridine; Development; Distal; Epithelial; Epithelial Cells; Epithelium; Event; Ferrets; Fibrosis; Funding; Gastrin releasing peptide; Gland; Goals; Graft Rejection; Harvest; Hilar; Histologic; Histopathology; Human; Immune; In Vitro; Inflammatory; Injury; Label; Laboratories; Lead; Left lung; Lung; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Lymphocyte; Mentors; Modeling; Nerve Endings; Neuroendocrine Cell; Neuroepithelial Bodies; Neuropeptides; Nucleotides; Organ Transplantation; Outcome; Pathogenesis; Pattern; Phenotype; Play; Population; Recording of previous events; Reperfusion Injury; Research; Research Personnel; Role; Sampling; Scientist; Signal Transduction; Site; Solid; Somatostatin; Staging; Stem cells; Substance P; Syndrome; Testing; Time; Transgenic Animals; Transplant Recipients; Transplantation; airway epithelium; base; cell injury; cell type; effective therapy; exhaustion; in vivo; indexing; injured airway; knockout animal; lung allograft; nerve supply; novel; prevent; progenitor; respiratory; response; response to injury; skills; stem; stem cell niche; stem cell population

DESCRIPTION (provided by applicant): The long-term goal of the investigator is to become a productive and independent clinician scientist with a well- funded laboratory focused on lung transplantation research. The immediate goal of the investigator is to acquire the skill set necessary to become an independent investigator. This proposal focuses on understanding the pathogenesis of obliterative bronchiolitis (OB) that develops in 50% of the recipients following lung transplantation within 5 years. We have developed a model of orthotopic left lung transplant that reproduces all aspect of human lung transplant histopathology, including development of OB. Using this novel model we propose to investigate whether airway epithelial stem cells respond abnormally following lung transplantation and to determine if this abnormal response contributes to the development of OB. Specifically, this proposal will focus on the contribution of denervation to aberrant calcitonin gene related peptide (CGRP) neuropeptide responses that control stem cell proliferation in the airways. The investigator's mentor, Dr. John Engelhardt, has a long-standing history in studying stem/progenitor cells in the lung and has studied airway biology in the ferret for more than a decade. Lung transplantation is a major treatment option for end-stage lung diseases. OB, which is considered to be a form of chronic rejection in the transplanted lung, prevents long-term survival as it affects almost one out of two recipients by five years. Once OB sets in the allograft, it is progressively fatal and there is no effective treatment available. The mechanisms that cause OB are unclear and it has been proposed that epithelial stem cell depletion may be a contributing factor. However, there is currently no research being done to test this hypothesis. We recently developed an orthotopic lung transplant model in the ferret that develops classic OB. We have also shown that CGRP, a known marker for the stem/progenitor celI niches in the distal airways, promotes proliferation and differentiation of slow-cycling airway stem cells into transient-amplifying cells with limited proliferative capacity. In this proposal we will address the following hypotheses: 1) In a transplanted lung, epithelial injury results in the aberrant recruitment and proliferation of slow- cycling stem cells at different sites within the donor lung/allograft. 2) In a transplanted lung, he CGRP response to injury is dysregulated due to the lack of innervation. 3) In a transplanted lung, dysregulation of CGRP levels leads to exhaustion of slow-cycling stem cells in the distal airways and, ultimately, an aberrant injury response. We expect that understanding the epithelial stem cells injury responses in the transplanted lung will clarify the pathogenesis of OB and thereby provide an opportunity to prevent or delay the development of OB in the allografts. Furthermore, our proposal will address several basic biologic questions about how innervations controls stem cell injury responses in the lung through neuropeptide signals. Such information may also be generally useful to the field of lung biology. PUBLIC HEALTH RELEVANCE: Lung transplantation is a viable treatment option for a variety of end-stage lung diseases. However, long-term survival following lung transplantation is limited by development of obliterative bronchiolitis (OB) in the allografts that is irreversible and unresponsive to therapy. Approximately 50% of the lung transplant recipients are affected by OB within 5 years of transplantation. Progress in the effective management of OB has been limited due to lack of appropriate animal models that reproduce the human OB phenotype in lung allografts. We have developed a ferret orthotopic lung transplant model that develops OB and will use this model to investigate how stem cells respond to injury in the transplanted lung. We will test the hypothesis that depletion of airway stem cells contributes to the development of OB in the allograft.

描述（由申请人提供）：研究者的长期目标是成为一名富有成效且独立的临床科学家，拥有一个资金充足的实验室，专注于肺移植研究。调查员的直接目标是获得成为独立调查员所需的技能。该提案的重点是了解闭塞性细支气管炎 (OB) 的发病机制，50% 的受者在肺移植后 5 年内会发生闭塞性细支气管炎 (OB)。我们开发了一种原位左肺移植模型，可再现人类肺移植组织病理学的各个方面，包括 OB 的发展。我们建议使用这种新模型来研究肺移植后气道上皮干细胞是否出现异常反应，并确定这种异常反应是否会导致 OB 的发生。具体来说，该提案将重点关注去神经支配对控制气道干细胞增殖的异常降钙素基因相关肽（CGRP）神经肽反应的贡献。研究人员的导师约翰·恩格尔哈特 (John Engelhardt) 博士在研究肺部干/祖细胞方面拥有悠久的历史，并且研究雪貂气道生物学已有十多年。肺移植是终末期肺病的主要治疗选择。 OB 被认为是移植肺中慢性排斥反应的一种形式，它会阻碍长期生存，因为它影响了几乎二分之一的人 接收者五年。一旦 OB 在同种异体移植物中形成，就会逐渐致命，并且没有有效的治疗方法。导致 OB 的机制尚不清楚，有人提出上皮干细胞耗竭可能是一个促成因素。然而，目前还没有任何研究来检验这一假设。我们最近在雪貂中开发了一种原位肺移植模型，可产生经典的 OB。我们还表明，CGRP（远端气道干/祖细胞微环境的一种已知标记物）可促进慢周期气道干细胞增殖和分化为增殖能力有限的瞬时扩增细胞。在本提案中，我们将提出以下假设：1）在移植肺中，上皮损伤导致供体肺/同种异体移植物内不同部位的慢循环干细胞异常募集和增殖。 2) 在移植的肺中，由于缺乏神经支配，CGRP 对损伤的反应失调。 3) 在移植肺中，CGRP 水平失调导致远端气道中慢循环干细胞耗尽，最终导致异常损伤反应。我们期望了解移植肺中上皮干细胞损伤反应将阐明 OB 的发病机制 从而提供预防或延缓同种异体移植物中 OB 发展的机会。此外，我们的提案将解决几个基本的生物学问题，即神经支配如何通过神经肽信号控制肺部干细胞损伤反应。此类信息对于肺生物学领域也可能普遍有用。 公共卫生相关性：肺移植是多种终末期肺病的可行治疗选择。然而，肺移植后的长期生存受到同种异体移植物中发生不可逆且对治疗无反应的闭塞性细支气管炎（OB）的限制。大约 50% 的肺移植受者在移植后 5 年内会出现 OB 的症状。由于缺乏在肺同种异体移植物中重现人类 OB 表型的适当动物模型，有效管理 OB 的进展受到限制。我们开发了一种雪貂原位肺移植模型，可产生 OB，并将使用该模型来研究干细胞如何应对移植肺损伤。我们将检验气道干细胞耗竭有助于同种异体移植物中 OB 发展的假设。