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Epithelial Progenitor Cell Dysfunction in the Fibroproliferative Process of CLAD

CLAD 纤维增殖过程中的上皮祖细胞功能障碍

基本信息

批准号：
10450043
负责人：
JOHN A BELPERIO
金额：
$ 46.8万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450043
关键词：
Acute Affect Allografting Alveolar Area Binding Biological Bronchiolitis Obliterans Cell Lineage Cells Cessation of life Chronic Clinical Data Clinical Trials Data Deposition Development Diagnosis Down-Regulation Environment Epithelial Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Foundations Functional disorder Future Human IL10RB gene Infection Inflammatory Injury Label Lead Leukocytes Lung Lung Transplantation Lung diseases Measures Mediating Medical Mesenchymal Modeling Mononuclear Mus Natural regeneration Outcome Pathway interactions Phase Phenotype Population Prevention therapy Prevention trial Process Procollagen Proliferating Proteins Pulmonary Fibrosis Reserve Cell Risk Role Sampling Signal Transduction Syndrome TP53 gene Transplant Recipients Transplantation airway epithelium base cell regeneration cell type design effective therapy epithelial stem cell exhaust fibrogenesis inflammatory milieu interleukin-22 interstitial loss of function lung allograft mouse model novel post-transplant pre-clinical prevent progenitor pulmonary function receptor receptor expression repaired stem cells translational study transplant model

项目摘要

Project Summary/Abstract Lung transplant (LT) is an option for advanced lung diseases; unfortunately, due to post-transplant complications, both infections and non-infections (i.e., rejections), which leads to chronic lung allograft dysfunction (CLAD) it is only a treatment and not a cure. The hallmark of CLAD is the displacement of normal epithelium by a relentless deposition of extracellular matrix. Currently, there are no effective therapies for the prevention or treatment of CLAD. This proposal will use both a novel mouse orthotopic-transplant-with-regrafting to model the pathobiology of CLAD and human translational studies to evaluate mechanisms that lead to epithelial progenitor cell (EPC) loss and fibrogenesis during CLAD. We have previously shown that a type 1/17 inflammatory environment promotes acute rejection (AR), while the type 2 fibroproliferative environment supports the development of fibrosis in CLAD. Our preliminary data suggests that loss of epithelial progenitor cell reserves (EPCR) leads to fibroplasia and CLAD. Additionally, we propose that IL-22, in part through a p53-dependent pathway, functions differently at different stages post-transplantation. During the early stages of allograft injury, IL-22 is beneficial by promoting EPCR expansion. However, later on, IL-22 influences fibroblasts thereby stimulating the development of fibrosis in CLAD. The consequence of IL-22 upon the lung allograft depends on the cell type on which its receptor is expressed. During the inflammatory type 1/17 phase, the EPCR expresses the heterodimeric IL-22 receptor (IL-22R1 and IL-10R2), while fibroblasts do not. Thus, during early injury stages post-LT, IL-22 mediates downregulation of p53 signaling just in epithelial cells, thereby allowing progenitor cells to proliferate and regenerate the lung epithelium. Conversely, when continued insults to the lung allograft leads to a fibroproliferative type 2 environment, the IL-22 receptor expression is induced on fibroblasts and reduced on EPCR. Thus, at this later stage, IL-22 interacts preferentially with its receptor on fibroblasts, skewing them towards an invasive, fibrotic phenotype resulting in CLAD. Our preliminary pre-clinical data in murine models suggest that manipulating IL-22 and p53 can affect the outcome of CLAD, either protective via promotion of EPC regeneration or harmful via promotion of fibroplasia. Moreover, we will insure the relevance of these pathways in humans using lung transplant (LT) recipients biological samples that include BALF protein and cultured fibroblasts as well as brushing of the allograft airway epithelial cells.

项目总结/文摘