MATRIX MEDIATORS OF WOUND HEALING

伤口愈合的基质介质

• 批准号: 6180499
• 负责人: LISA F STAIANO-COICO
• 金额: $ 34.74万
• 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/6180499
• 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）在皮肤外伤时， 受伤的表皮内引发了一系列复杂的事件， “激活”驻留角质形成细胞 (NHK) 并导致细胞发生改变 生长和运动能力。 尽管触发的明确信号 基底角质形成细胞对迁移和再生途径的承诺 成熟度仍然很大程度上未知，失去对基底的粘附 膜是表皮迁移和分化的一个重要方面 可能涉及“抗粘附”基质蛋白的调节表达。 研究人员确定了一种抗粘附蛋白 再上皮化过程的潜在调节剂和 NHK 中的再生成熟是 SPARC（也称为骨连接蛋白和 BM-40) SPARC 是一种分布广泛且高度保守的细胞外 参与过程的基质 (ECM) 相关糖蛋白 需要组织重塑。 SPARC 基因敲除小鼠的最新证据 表明 SPARC 表达缺失与真皮缺陷有关 伤口修复。 稳定反义中 SPARC 表达的抑制 转染子严重抑制基础 NHK 的迁移能力 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一个关键事件。 伤口愈合后 随着NHK的关闭，NHK开始分化并垂直向 皮肤表面。 抗粘连事件也与此有关 过程;研究人员之前已经表明 SPARC 是专门 在失去对基底膜的粘附之前诱导，随后 NHK 的终末分化。 该项目的具体目标是： I. 确定 SPARC 表达和细胞类型的机制 NHK 亚群中表达的特异性： (A) 横向 因受伤而迁移； (B) 垂直迁移响应 由 NaBr 诱导的再生成熟。 二. 通过以下方式确定机制 NHK 中 SPARC 表达的分子扰动会改变： (A) NHK 细胞周期动力学：(B) NHK 对受伤的反应； (C) NHK 差异化。 三． 确定 SPARC 的分子扰动如何 表达影响角质形成细胞伤口相关变化的调节 基因表达。