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)关于皮肤创伤， 一系列复杂的事件在受伤的表皮内启动， “激活”常驻角质形成细胞(NHKs)并导致细胞改变 生长和动力。尽管触发的决定性信号 基底层角质形成细胞对迁移和再生途径的承诺 成熟度在很大程度上仍不清楚，对基底的粘附力的丧失 膜是表皮迁移和分化的关键方面， 可能涉及“抗粘连”基质蛋白的调节表达。 一种抗粘连蛋白，研究人员已确定为一种 再上皮化和上皮化过程的潜在调节者 NHKs的再生成熟是SPARC(也称为骨联素和 BM-40)SPARC是一种分布广泛、高度保守的胞外生物 与细胞外基质(ECM)相关的糖蛋白 需要组织重塑。SPARC基因敲除小鼠的最新证据 提示SPARC表达的丧失与皮肤的缺陷有关 伤口修复。稳定反义抑制SPARC基因表达的研究 转染剂严重抑制基础NHKs在 对伤害的反应，从而支持他们的假设，即 SPARC是表皮创面修复过程中的关键事件。后续伤口 关闭后，NHK开始分化并垂直迁移到 皮肤的表面。防粘连事件也与此相关 过程；调查人员之前已经表明，SPARC是专门 在失去与基底膜的粘连之前诱导，随后 NHKs的终末分化。该项目的具体目标是：I。 确定SPARC表达和细胞类型的潜在机制 NHKs亚群表达的特异性：(A)侧向 应对伤害的迁移和；(B)应对伤害的垂直迁移 NaBrR诱导的再生成熟。II.通过以下方式确定机制 NHK中SPARC表达的哪种分子扰动改变：(A)NHK 细胞周期动力学：(B)NHK对创伤的反应；(C)NHK 差异化。确定SPARC的分子微扰如何 表达影响角质形成细胞创伤相关变化的调节 基因表达。