S100A4 Regulation of IPF Mesenchymal Progenitor Cell Fibrogenicity

S100A4 IPF 间充质祖细胞纤维原性的调节

基本信息

批准号：
9900051
负责人：
CRAIG A HENKE
金额：
$ 60.13万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900051
关键词：
Alveolar Autocrine Communication Automobile Driving Bleomycin CD44 gene Cell Cycle Cell Differentiation process Cell Nucleus Cell Proliferation Cell physiology Cell surface Cells Clinical Collagen Complex Critical Pathways Cytoplasm Data Deposition Development Disease Disease Progression Extracellular Matrix Extracellular Space Fibroblasts Fibrosis Human Hyaluronan In Vitro Integrins Karyopherins Knowledge Lesion by Morphology Link Location Lung Lung diseases Maintenance Mediating Mesenchymal Mesenchymal Stem Cells Methyltransferase Modeling Molecular Mus Myofibroblast Nonmuscle Myosin Type IIA Nuclear Pathologic Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmacotherapy Phenotype Physical shape Property Proteins Publishing Pulmonary Fibrosis Regulation Reporting Role S100A4 gene Sentinel Signal Pathway Signal Transduction Specimen Structure Structure of parenchyma of lung Subgroup Supporting Cell TP53 gene Therapeutic Treatment Efficacy Work Xenograft Model Xenograft procedure base cancer cell cell motility design experimental study extracellular idiopathic pulmonary fibrosis in vivo macrophage member mouse model multicatalytic endopeptidase complex non-muscle myosin paracrine recruit self-renewal

项目摘要

PROJECT SUMMARY Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting fibrogenic signaling pathways, Idiopathic Pulmonary Fibrosis (IPF) remains a major unsolved clinical problem. One reason for this is that currently available anti-fibrotic agents slow but do not arrest fibrotic progression. To fully arrest fibrotic progression, its obligatory drivers need to be identified. We have made several recent discoveries studying primary cells and ECM from IPF patients that illuminate a path forward toward understanding mechanisms driving the relentless progression of fibrosis following disease initiation. We learned that fibrosis progression involves cell-intrinsic/autonomous mechanisms. Cell-autonomous fibrogenicity was established by our discovery of fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients with IPF and that S100A4 mediates their fibrogenicity. Our data indicate that fibrogenic mesenchymal cells residing in a fibrogenic ECM is a key driver of fibrotic progression in the human IPF lung. We have recently discovered that the sentinel morphologic lesion of IPF, the fibroblastic focus, is a polarized structure with an active fibrotic front that contains IPF MPCs, their transit amplifying progeny and activated macrophages residing in a hyaluronan (HA)-rich extracellular matrix (ECM) that supports their pathological properties. In contrast, the core of the fibroblastic focus is a collagen-rich region containing non-cycling myofibroblasts actively synthesizing and depositing ECM. In this proposal we will: i) examine the role of nuclear, cytoplasmic and extracellular S100A4 in regulating the fibrogenicity of IPF MPCs and their progeny; ii) define the key components of the fibrogenic niche microenvironment that regulate S100A4 function; and iii) identify subgroups of phenotypically distinct MPCs within the fibrogenic niche that cooperate to drive fibrotic progression. Two Aims are proposed: In Aim 1 we will determine the molecular mechanism by which the HA-CD44 axis regulates nuclear S100A4 function and MPC self-renewal and identify subgroups of IPF MPCs based on SSE4 and HA cell surface expression; in Aim 2 we will determine the role of cytoplasmic S100A4 in acquisition of a motile phenotype as IPF MPCs differentiate to IPF fibroblasts; and examine the role of IPF MPC progeny-derived extracellular S100A4 in driving fibrotic progression. New knowledge about subgroups of fibrogenic MPCs, the cells that support them within the active fibrotic front, and fibrogenic signals in the microenvironment; has the potential to greatly advance the design of therapeutics that fully arrest fibrotic progression and even reverse established fibrosis. !

项目摘要尽管药物疗法靶向的最新进展，患者预后的改善适中纤维化信号通路，特发性肺纤维化（IPF）仍然是一个主要未解决的临床问题。原因之一是目前可用的抗纤维化剂缓慢，但不会阻止纤维化进展。到完全阻止纤维化进展，需要确定其强制性驱动因素。我们最近做了几个从IPF患者中研究原代细胞和ECM的发现，从而照亮了前进的路径理解疾病开始后促进纤维化的不断进展的机制。我们了解到纤维化进展涉及细胞中/自主机制。细胞自主纤维化是通过我们发现患者肺中的纤维化间充质祖细胞（MPC）建立的使用IPF，S100A4介导了其纤维化。我们的数据表明纤维化间充质细胞居住在纤维化ECM中是人IPF肺纤维化进展的关键驱动力。我们最近有发现IPF的前哨形态病变是成纤维细胞焦点，是一个极化结构，活跃的纤维化阵线包含IPF MPC，其运输放大后代和激活的巨噬细胞驻留在支持其病理特性的透明质酸（HA） - 富含细胞外基质（ECM）中。在对比，成纤维细胞焦点的核心是富含胶原蛋白的区域，其中包含非循环的肌纤维细胞积极合成和存放ECM。在此提案中，我们将：i）检查核，细胞质的作用和细胞外S100A4在调节IPF MPC及其后代的纤维化方面； ii）定义钥匙调节S100A4功能的纤维化小众微环境的组成部分； iii）确定亚组在纤维化小众内的表型不同的MPC的合作，以驱动纤维化进展。二提出了目标：在AIM 1中，我们将确定HA-CD44轴调节的分子机制核S100A4功能和MPC自我更新，并根据SSE4和HA确定IPF MPC的亚组细胞表面表达；在AIM 2中，我们将确定细胞质S100A4在获取运动中的作用 IPF MPC的表型与IPF成纤维细胞区分开；并检查IPF MPC后代衍生的作用驱动纤维化进展的细胞外S100A4。有关纤维化MPC亚组的新知识，在活跃的纤维化锋中支持它们的细胞，以及微环境中的纤维化信号；有极大地推进完全阻碍纤维化进展甚至反向的治疗剂设计的潜力已建立的纤维化。呢