MATRIX MEDIATORS OF WOUND HEALING

描述：（改编自申请人的摘要）皮肤创伤后， 在受伤的表皮内引发复杂的级联事件， “激活”常驻角质形成细胞（NHK）并导致改变的细胞增殖。 生长和运动。 虽然触发的决定性信号 基底角质形成细胞向迁移和再生途径的定向 成熟仍然在很大程度上是未知的，附着在基底上的丧失 膜是表皮迁移和分化的关键方面， 可能涉及“抗粘附”基质蛋白的调节表达。 一种抗粘附蛋白，研究人员已经确定为 上皮再生过程的潜在调节剂， NHK中的再生成熟是骨粘连蛋白（也称为骨粘连蛋白， BM-40）是一种广泛分布和高度保守的细胞外 基质（ECM）相关糖蛋白，涉及过程 需要组织重塑。 最近的证据表明， 表明，表达缺失与真皮缺陷有关， 伤口修复 在稳定的反义寡核苷酸中抑制p53表达 转染子严重抑制了基础NHK迁移入细胞的能力， 因此支持了他们的假设， 表皮损伤是表皮创伤修复的关键事件。 下列伤口 关闭时，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;调查人员先前已经表明， 在失去对基底膜的粘附之前诱导， NHK的终末分化。 本项目的具体目标是：一。 确定表达的潜在机制和细胞类型 在经历以下过程的NHK亚群中表达的特异性：（A）侧向 （B）响应于创伤的垂直迁移， NaBr诱导的再生成熟。 二. 通过以下方式确定机制： 其中NHK中的NHK表达的分子扰动改变了：（A）NHK 细胞周期动力学：（B）NHK对创伤的反应;和（C）NHK 分化 三. 确定分子微扰是如何 表达影响角质形成细胞中创伤相关变化的调节 基因表达。

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.