MATRIX MEDIATORS OF WOUND HEALING

伤口愈合的基质介质

• 批准号: 2562606
• 负责人: LISA F STAIANO-COICO
• 金额: $ 34.78万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2562606
• 关键词: basement membrane; cell adhesion; cell differentiation; cell growth regulation; cell migration; cell type; collagen; epithelium; extracellular matrix proteins; gene expression; gene targeting; genetic regulation; genetically modified animals; glycoprotein biosynthesis; in situ hybridization; keratinocyte; laboratory mouse; messenger RNA; plasminogen activator inhibitors; protein structure function; tissue /cell culture; transfection /expression vector; wound healing

DESCRIPTION: (Adapted from the applicant's abstract) Upon cutaneous trauma, a complex cascade of events is initiated within the wounded epidermis, "activating" resident keratinocytes (NHKs) and resulting in altered cellular growth and motility. Although the definitive signals that trigger commitment of basal keratinocytes to a pathway of migration and regenerative maturation remain largely unknown, the loss of adherence to the basement membrane is a critical aspect of epidermal migration and differentiation and likely involves regulated expression of "anti-adhesive" matrix proteins. One anti-adhesive protein that the investigators have identified as a potential regulator of the processes of re-epithelialization and regenerative maturation in NHKs is SPARC (also known as osteonectin and BM-40) SPARC is a widely distributed and highly conserved extracellular matrix (ECM)-associated glycoprotein that has been implicated in processes requiring tissue remodeling. Recent evidence in SPARC knockout mice suggests that loss of SPARC expression is associated with a defect in dermal wound repair. Inhibition of SPARC expression in stable anti-sense tranfectants severely inhibits the ability of basal NHKs to migrate in response to wounding thus supporting their hypothesis that expression of SPARC is a critical event in epidermal wound repair. Following wound closure, NHKs begin to differentiate and vertically migrate toward the surface of the skin. Anti-adhesive events are also associated with this process; the investigators have shown previously that SPARC is specifically induced prior to loss of adherence to the basement membrane and subsequent terminal differentiation of NHKs. Specific Aims for this project are: I. Determine the mechanisms underlying SPARC expression and the cell-type specificity of expression in subpopulations of NHKs undergoing: (A) Lateral migration in response to wounding and; (B) Vertical migration in response to regenerative maturation induced by NaBr. II. Ascertain the mechanism by which molecular perturbation of SPARC expression in NHKs alters: (A) NHK cell cycle kinetics: (B) NHK response to wounding; and (C) NHK differentiation. III. Determine how molecular perturbation of SPARC expression affects the regulation of wound-related changes in keratinocyte gene expression.

描述：（改编自申请人的摘要）皮肤创伤， 在受伤的表皮中启动了一系列复杂的事件， “激活”居民角质形成细胞（NHK），导致细胞改变 增长和运动。 虽然触发的确定信号 基底角质形成细胞对迁移和再生途径的承诺 成熟仍然未知，遵守地下室的丧失 膜是表皮迁移和分化和 可能涉及“抗粘附”基质蛋白的调节表达。 研究人员已确定为一种抗粘附蛋白 重新上皮化过程的潜在调节器和 NHK中的再生成熟是SPARC（也称为骨质蛋白和 BM-40）SPARC是一个广泛的分布和高度保守的细胞外 基质（ECM）相关的糖蛋白与过程有关 需要组织重塑。 SPARC淘汰小鼠的最新证据 表明SPARC表达的损失与真皮缺陷有关 伤口修复。 在稳定的反义中抑制SPARC表达 三角体严重抑制了基础NHK迁移的能力 对伤害的反应，从而支持他们的假设 SPARC是表皮伤口修复中的关键事件。 伤口后 关闭，NHK开始区分并垂直迁移到 皮肤表面。 抗粘性事件也与此相关 过程;研究人员先前已经表明，SPARC是专门的 在失去对地下膜的粘附之前引起的诱导 NHK的终端分化。 该项目的具体目标是：I。 确定SPARC表达和细胞类型的基础机制 在进行NHK的亚群中表达的特异性：（a）横向 响应伤害的迁移； （b）响应于 NABR诱导的再生成熟。 ii。 通过确定机制 NHK中SPARC表达的哪种分子扰动变化：（a）NHK 细胞周期动力学：（b）NHK对伤害的反应； （c）NHK 分化。 iii。 确定SPARC的分子扰动 表达会影响角质形成细胞伤口相关的变化的调节 基因表达。