Paradigms of Wound Healing and Fibrosis in the Eye

眼睛伤口愈合和纤维化的范例

基本信息

批准号：
8516041
负责人：
A. Sue Menko
金额：
$ 37.44万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516041
关键词：
Adult Antibodies Antigens Applications Grants Cataract Extraction Cell physiology Cells Cellular biology Characteristics Chick Embryo Cornea Cytokine Signaling DNA biosynthesis Debridement Developmental Process Disease Embryo Enzyme Induction Epiblast Epigenetic Process Epithelial Epithelial Cells Epithelium Eye Fibrosis Germ Layers Healed Hematopoietic Injury Investigation Knowledge Link Mediating Mesenchymal Mesenchymal Stem Cells Modeling Movement Myofibroblast Occupations Paper Phenotype Play Polyploidy Population Population Sizes Process Property Proteins Rattus Recruitment Activity Reporting Role Signal Pathway Signal Transduction Site Source Stem cells Surface Antigens Time Tissues Vimentin Wound Healing capsule cell injury cell type corneal epithelium corneal scar gene repression healing injury and repair lens novel precursor cell progenitor repaired response response to injury tissue regeneration transcription factor transdifferentiation wound

项目摘要

Currently the identity of precursors of the mesenchymal cells involved in wound healing and fibrosis are under debate. We propose a novel paradigm in which these cells descend from a unique subpopulation of repair progenitor cells that coexist normally with the cells of epithelial tissues. We have shown the presence of these repair cells in the lens and cornea. In the lens these repair progenitor cells rapidly respond to injury by expanding their population size through a mechanism independent of DNA replication, but likely related to their unusual characteristic of polyploidy. The signals that mediate the expansion of the progenitor cells, their reprogramming to a repair phenotype and the rapid targeting of the repair cells to the wound edge are unknown. While the repair cells function at the site of injury as regulators of the healing process, they also have the potential to trandifferentiate to a myofibroblast phenotype, the cell type linked to fibrosis. This proposal examines this novel wound healing paradigm in both lens and cornea injury models with the following questions: 1) Are the repair progenitor cells novel descendents of a hematopoietic lineage?; 2) What is the mechanism by which repair cell progenitors rapidly expand in response to injury of their host epithelium?; 3) How are mesenchymal progenitor cells signaled to migrate to the wound edge?; 4) What is the fate of the mesenchymal cells after they complete their job of regulating wound repair?; and 5) What are the conditions that induce the repair cells to acquire the mature myofibroblast phenotype associated with disease states such as fibrosis? These studies are expected to have a major impact in the fields of cell biology and wound healing by shifting the study of the regulators of wound healing and source of myofibroblasts to this novel progenitor population.

目前参与伤口愈合和纤维化的间充质细胞前体的身份尚不清楚辩论。我们提出了一种新的范例，其中这些细胞源自独特的修复亚群与上皮组织细胞正常共存的祖细胞。我们已经证明了这些的存在修复晶状体和角膜中的细胞。在晶状体中，这些修复祖细胞通过以下方式快速对损伤做出反应：通过一种独立于 DNA 复制的机制扩大它们的种群规模，但可能与它们的多倍体的不寻常特征。介导祖细胞扩增的信号，它们的重编程为修复表型以及修复细胞快速靶向伤口边缘未知。虽然修复细胞在损伤部位发挥愈合过程调节器的作用，但它们也有潜力转分化为肌成纤维细胞表型，即与纤维化相关的细胞类型。这该提案通过以下内容在晶状体和角膜损伤模型中检查了这种新颖的伤口愈合范例问题：1）修复祖细胞是造血谱系的新后代吗？ 2）什么是修复细胞祖细胞响应宿主上皮损伤而快速扩增的机制？ 3）间充质祖细胞如何向伤口边缘发出信号迁移？ 4) 命运如何间充质细胞完成调节伤口修复的工作后？ 5) 条件是什么诱导修复细胞获得与疾病状态相关的成熟肌成纤维细胞表型作为纤维化？这些研究预计将对细胞生物学和伤口愈合领域产生重大影响通过将伤口愈合调节因子和肌成纤维细胞来源的研究转移到这种新的祖细胞上人口。