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. !

项目概要尽管靶向药物治疗的最新进展使患者的治疗结果略有改善纤维化信号通路，特发性肺纤维化（IPF）仍然是一个未解决的主要临床问题。原因之一是目前可用的抗纤维化药物可以减缓但不能阻止纤维化进展。到为了完全阻止纤维化进展，需要确定其必然的驱动因素。我们最近做了几个研究 IPF 患者原代细胞和 ECM 的发现照亮了前进的道路了解疾病发生后驱动纤维化不断进展的机制。我们了解到纤维化进展涉及细胞内在/自主机制。细胞自主纤维原性是通过我们在患者肺部发现纤维化间充质祖细胞（MPC）而建立的与 IPF 相关，并且 S100A4 介导其纤维形成性。我们的数据表明，纤维化间充质细胞存在于纤维化 ECM 中是人类 IPF 肺部纤维化进展的关键驱动因素。我们最近有发现 IPF 的前哨形态病变，即成纤维细胞灶，是一种极化结构，具有活性纤维化前沿，包含 IPF MPC、其转运放大后代和活化的巨噬细胞存在于富含透明质酸 (HA) 的细胞外基质 (ECM) 中，支持其病理特性。在相比之下，成纤维细胞焦点的核心是富含胶原蛋白的区域，其中含有非循环肌成纤维细胞积极合成和沉积ECM。在本提案中，我们将： i) 检查细胞核、细胞质的作用和细胞外 S100A4 在调节 IPF MPC 及其后代的纤维形成中的作用； ii) 定义密钥调节 S100A4 功能的纤维化生态位微环境的组成部分； iii) 确定亚组纤维化生态位内表型不同的 MPC 共同驱动纤维化进展。二提出的目标：在目标 1 中，我们将确定 HA-CD44 轴调节的分子机制核S100A4功能和MPC自我更新并基于SSE4和HA识别IPF MPC亚群细胞表面表达；在目标 2 中，我们将确定细胞质 S100A4 在获得运动能力中的作用 IPF MPC 分化为 IPF 成纤维细胞时的表型；并检查 IPF MPC 后代的作用细胞外 S100A4 驱动纤维化进展。关于纤维化 MPC 亚群的新知识在活跃的纤维化前沿内支持它们的细胞，以及微环境中的纤维化信号；有有潜力极大地推进完全阻止甚至逆转纤维化进展的治疗方法的设计已形成纤维化。！