Epithelial Stem Cells in Lung Transplantation

上皮干细胞在肺移植中的应用

• 批准号: 8656428
• 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/8656428
• 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.

描述（由申请人提供）：研究者的长期目标是成为一名多产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，在50%的受者在肺移植后5年内发展。我们已经建立了一个原位左肺移植模型，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。使用这种新的模型，我们建议调查是否气道上皮干细胞肺移植后的异常反应，并确定这种异常反应是否有助于OB的发展。具体来说，这项建议将集中在贡献的失神经异常降钙素基因相关肽（CGRP）神经肽反应，控制干细胞增殖的气道。研究者的导师John Engelhardt博士在研究肺中的干/祖细胞方面有着悠久的历史，并在雪貂中研究气道生物学已有十多年。肺移植是终末期肺部疾病的主要治疗选择。OB被认为是移植肺中慢性排斥反应的一种形式，由于它几乎影响了两个中的一个， 五年后的收件人。一旦OB在同种异体移植物中形成，它是逐渐致命的，并且没有有效的治疗方法。引起OB的机制尚不清楚，已经提出上皮干细胞耗竭可能是一个促成因素。然而，目前还没有研究来验证这一假设。我们最近开发了一种在雪貂中进行原位肺移植的模型，该模型发展为典型的OB。我们还发现，CGRP，一个已知的标记物干/祖细胞在远端气道壁龛，促进增殖和分化的慢循环气道干细胞的瞬时扩增细胞有限的增殖能力。在本提案中，我们将解决以下假设：1）在移植的肺中，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的异常募集和增殖。 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)在移植的肺中，CGRP水平的失调导致远端气道中慢循环干细胞的耗尽，并最终导致异常的损伤反应。我们希望了解上皮干细胞在移植肺中的损伤反应将有助于阐明OB的发病机制 从而提供了防止或延迟同种异体移植物中OB发展的机会。此外，我们的建议将解决几个基本的生物学问题，神经支配如何通过神经肽信号控制肺中的干细胞损伤反应。这种信息通常也可用于肺生物学领域。