Pericyte mobilisation and functional plasticity in chronic allergic airway disease

慢性过敏性气道疾病的周细胞动员和功能可塑性

• 批准号: MR/K011375/1
• 负责人: Jill Johnson
• 金额: $ 59.59万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK011375%2F1
• 关键词: Pericyte; mobilisation; functional; plasticity; chronic

The research project described here ultimately aims to answer fundamental questions on the biology of structural cells (pericytes) associated with the blood vessels in the lung and how these cells contribute to the pathogenesis of allergic asthma. Specifically, this research proposal aims to investigate the hypothesis that chronic allergic inflammation modulates pericyte functional plasticity and mobilisation in a mouse model of allergic asthma. The primary goal is to identify the mechanisms and functional consequences of pericyte mobilisation in allergic asthma, and also to assess the stem cell capacity of these cells in the healthy and diseased lung. The results from these experiments will not only increase our understanding of the role of lung-resident structural cells in asthma pathology, but will also provide insight into a previously unexplored therapeutic target in allergic asthma.Aim 1My preliminary experiments have demonstrated that pericytes detach from the blood vessels associated with the large airways and migrate toward the basement membrane of the airway, where they incorporate into the smooth muscle of the airway wall. In the house dust mite-driven model of asthma employed in this project, the development of airway smooth muscle thickening coincides temporally with a significant increase in airway resistance. In fact, an association between airway smooth muscle thickening and airway hyperreactivity (wheezing) has been demonstrated in a number of clinical studies. However, the mechanisms that cause airway smooth muscle thickening are incompletely understood. This part of the project is designed to determine the chemotactic mechanisms responsible for recruiting pericytes to the airway wall, thus providing mechanisms insight into their role in airway remodelling. Aim 2Pericytes have been shownfound to possess progenitor/stem cell capacity, similar to the features of bone-marrow derived mesenchymal stem cells. This supports the idea that although pericytes may promote pathological events in disease progression (i.e. airway remodelling), they may also possess immunomodulatory capacity as has been shown for mesenchymal stem cells derived from other parts of the body. In the second part of this project, I plan to use techniques already established in the lab of Prof Sara Rankin, my mentor in the Leukocyte Biology group, to isolate pericytes from the lungs of healthy and asthmatic mice and to evaluate their expression of stem cell markers, their capacity to differentiate into various mesenchymal cell lineages (adipocytes, chondrocytes, osteoblasts and smooth muscle cells) and finally their ability to modulate allergen-specific immune responses. The results from this project will not only inform on the identity and characteristics of a type of lung-resident mesenchymal stem cells, but will also provide valuable knowledge on the capacity of these cells to modulate an inflammatory response.Aim 3TThis part of the project aims to investigate the feasibility ofmodifying the behavior of pericytes as a therapeutic intervention in allergic asthma. This will be achieved by employing adenovirus vectors, both obtained commercially and provided by my collaborator, Prof Ulf Eriksson at the Karolinska Institute. Informed by the results of the first two parts of this study, the gene expression of pericytes will be modified both in vitro and in vivo with the goal of either inhibiting their mobilisation from the blood vessels and incorporation into smooth muscle, or to enhance their immunomodulatory capacity and thereby serve as a negative regulator of the detrimental structural changes that occur in the asthmatic respiratory system.

本文描述的研究项目最终旨在回答与肺血管相关的结构细胞（周细胞）生物学的基本问题，以及这些细胞如何促进过敏性哮喘的发病机制。具体而言，本研究计划旨在研究慢性过敏性炎症调节过敏性哮喘小鼠模型中周细胞功能可塑性和动员的假设。主要目的是确定过敏性哮喘中周细胞动员的机制和功能后果，并评估健康和患病肺中这些细胞的干细胞能力。这些实验的结果不仅将增加我们对肺结构细胞在哮喘病理学中的作用的理解，而且还将提供对过敏性哮喘中以前未探索的治疗靶点的深入了解。目的1我的初步实验已经证明，周细胞从与大气道相关的血管分离并向气道的基底膜迁移，在那里它们结合到气道壁的平滑肌中。在这个项目中采用的室内尘螨驱动的哮喘模型中，气道平滑肌增厚的发展与气道阻力的显著增加在时间上一致。事实上，气道平滑肌增厚和气道高反应性（喘息）之间的关联已在许多临床研究中得到证实。然而，导致气道平滑肌增厚的机制还不完全清楚。本项目的这一部分旨在确定负责招募周细胞到气道壁的趋化机制，从而提供了解周细胞在气道重塑中作用的机制。目的2周细胞具有与骨髓间充质干细胞相似的祖细胞/干细胞能力。这支持了这样的想法，即虽然周细胞可以促进疾病进展中的病理事件（即气道重塑），但它们也可以具有免疫调节能力，如已经显示的来自身体其他部位的间充质干细胞。在这个项目的第二部分，我计划使用我在白细胞生物学小组的导师Sara兰金教授的实验室已经建立的技术，从健康和哮喘小鼠的肺部分离周细胞，并评估它们的干细胞标志物表达，它们分化成各种间充质细胞谱系的能力（脂肪细胞、软骨细胞、成骨细胞和平滑肌细胞）以及最终它们调节过敏原特异性免疫应答的能力。该项目的结果不仅将告知一种类型的肺驻留间充质干细胞的身份和特征，但也将提供有价值的知识，这些细胞的能力，以调节炎症respons.Aim 3 T这部分项目的目的是调查的可行性ofmodifying周细胞的行为作为一种治疗干预过敏性哮喘。这将通过使用腺病毒载体来实现，这两种载体都是商业获得的，也是由我的合作者，卡罗林斯卡研究所的乌尔夫·埃里克森教授提供的。根据本研究前两部分的结果，周细胞的基因表达将在体外和体内进行修饰，目的是抑制其从血管中动员并掺入平滑肌，或增强其免疫调节能力，从而作为哮喘呼吸系统中发生的有害结构变化的负调节剂。

项目成果

Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma.

• DOI: 10.1152/ajplung.00286.2014
• 发表时间: 2015-04-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Johnson JR;Folestad E;Rowley JE;Noll EM;Walker SA;Lloyd CM;Rankin SM;Pietras K;Eriksson U;Fuxe J
• 通讯作者: Fuxe J

Periostin Expression Is Elevated in HDM-Driven Allergic Airway Disease and Associated with Increased Pericyte Migration

HDM 驱动的过敏性气道疾病中 Periostin 表达升高，并与周细胞迁移增加相关

• DOI: 10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4495
• 发表时间: 2021
• 作者: Johnson J

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination.

• DOI: 10.1084/jem.20120662
• 发表时间: 2013-03-11
• 期刊: The Journal of experimental medicine
• 作者: Anderberg C;Cunha SI;Zhai Z;Cortez E;Pardali E;Johnson JR;Franco M;Páez-Ribes M;Cordiner R;Fuxe J;Johansson BR;Goumans MJ;Casanovas O;ten Dijke P;Arthur HM;Pietras K
• 通讯作者: Pietras K

Inflammation-Induced Pericyte Dysfunction Is Abrogated by Interfering with the CXCL12/CXCR4 Signaling Pathway

通过干扰 CXCL12/CXCR4 信号通路消除炎症引起的周细胞功能障碍

• DOI: 10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4490
• 发表时间: 2021
• 作者: Johnson J

Matricellular Protein Periostin Promotes Pericyte Migration in Fibrotic Airways.

• DOI: 10.3389/falgy.2021.786034
• 发表时间: 2021
• 期刊: Frontiers in allergy
• 作者: Bignold RE;Johnson JR
• 通讯作者: Johnson JR