Epithelial Stem Cells in Lung Transplantation

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和独立的临床科学家，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一名独立调查员所必需的技能。该建议的重点是了解闭塞性细支气管炎（OB）的发病机制，该疾病在50%的肺移植后5年内发生。我们开发了一种原位左肺移植模型，该模型再现了人类肺移植组织病理学的所有方面，包括OB的发展。使用这种新模型，我们建议研究肺移植后气道上皮干细胞是否有异常反应，并确定这种异常反应是否有助于OB的发展。本研究将聚焦于去神经支配在控制气道干细胞增殖的异常降钙素基因相关肽（CGRP）神经肽反应中的作用。研究者的导师约翰·恩格尔哈特博士在研究肺中的干细胞/祖细胞方面有着悠久的历史，他研究雪貂的气道生物学已有十多年了。肺移植是终末期肺部疾病的主要治疗选择。OB被认为是移植肺的一种慢性排斥反应，它影响了几乎二分之一的患者的长期生存

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.