Matrix Regulation of Cell Function During Wound Healing

伤口愈合过程中细胞功能的基质调节

• 批准号: 7098119
• 负责人: LIVINGSTON VAN DE WATER
• 金额: $ 27万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098119
• 关键词: biological signal transduction; cell differentiation; cell migration; cell proliferation; chimeric proteins; clinical research; extracellular matrix proteins; fibroblasts; fibronectins; gene induction /repression; human tissue; immunocytochemistry; inhibitor /antagonist; integrins; intermolecular interaction; laboratory mouse; monoclonal antibody; protein structure function; scars; site directed mutagenesis; skin; tissue /cell culture; transforming growth factors; wound healing

DESCRIPTION (provided by applicant): Pathogenic scarring and fibrosis represent important clinical problems with potentially serious consequences for patients, including impairment of normal tissue regeneration and neighboring tissue function. Our long term goal is to identify the critical regulatory mechanisms that govern fibroblast differentiation into myofibroblasts and thereby develop new strategies to control scarring and fibrosis. Although TGF-beta is a critical component of this mechanism, current evidence suggests that both mechanical stresses and EIIIAcontaining fibronectins (FNs) are important. The EIIIA (or ED-A) segment is one of a series of spring-like segments within FN hypothesized to transduce mechanical signals. The specific aims of this proposal are to target myofibroblast differentiation by eliminating EIIIA from cellular FN in healing wounds and to identify EIIIA-dependent intracellular targets that control myofibroblast differentiation. Using EIIIA null and wild type mice, we will examine the process of fibroblast differentiation and myofibroblast function utilizing histology, immunohistochemistry, quantitative protein analyses and tensiometry. We will also test the impact of mechanical force and flanking FN sequences on EIIIA- integrin interactions, in vitro. Experiments performed with fibroblasts isolated from null or wild type mice, as well as established human lines, will determine how the EIIIA-containing FNs, relevant integrins and signaling proteins regulate myofibroblast differentiation. Findings obtained from this work will fill impotant gaps in understanding myofibroblast regulation and suggest new therapeutic strategies to modulate fibrosis.

描述(由申请人提供)： 病理性瘢痕和纤维化是重要的临床问题，对患者具有潜在的严重后果，包括正常组织再生和邻近组织功能的损害。我们的长期目标是确定控制成纤维细胞分化为肌成纤维细胞的关键调控机制，从而开发控制瘢痕形成和纤维化的新策略。虽然转化生长因子-β是这一机制的关键组成部分，但目前的证据表明，机械应力和含有纤维连接蛋白(FN)的EIIIA都是重要的。EIIIA(或ED-A)节段是FN内一系列弹簧状节段之一，假设用于传递机械信号。这项建议的具体目的是通过从愈合伤口的细胞FN中清除EIIIA来靶向肌成纤维细胞的分化，并确定控制肌成纤维细胞分化的依赖于EIIIA的细胞内靶点。我们将以EIIIA基因缺失和野生型小鼠为研究对象，利用组织学、免疫组织化学、定量蛋白质分析和张力测量等方法研究成纤维细胞的分化过程和肌成纤维细胞的功能。我们还将在体外测试机械力和侧翼FN序列对EIIIA-整合素相互作用的影响。用从空白或野生型小鼠以及已建立的人类系分离的成纤维细胞进行的实验，将确定含有EIIIA的FN、相关整合素和信号蛋白如何调节肌成纤维细胞的分化。这项工作的发现将填补在了解肌成纤维细胞调节方面的重要空白，并建议新的治疗策略来调节纤维化。