ROLE OF ACTIN CYTOSKELETON ON UVA INDUCED APOPTOSIS

细胞凋亡发生在各种生理和病理状态下 条件。这对于维持人体的动态平衡至关重要。 皮肤，不适当的细胞凋亡被牵连在 多种皮肤病的发病机制。细胞凋亡调节细胞周期 在从颗粒化到颗粒化的转变过程中细胞密度降低 瘢痕组织和伤口愈合过程中的异常细胞凋亡 归因于增生性瘢痕和瘢痕疙瘩的发展。 细胞凋亡可能对紫外线诱导的皮肤癌的发展具有保护作用 通过选择性地摧毁受阳光损伤的角质形成细胞。基因突变 监测机制的组成部分，如P53和BD-2，提供 细胞有机会逃脱凋亡并发育成 非黑色素瘤皮肤癌。已经观察到早期的细胞凋亡。 在糖尿病伤口中，有助于钝化伤口愈合。因此， 改变细胞凋亡的开始或程度的操作可以 有可能提供治疗干预措施，用于治疗 各种皮肤病。因此，重要的是要描绘出 这一多步骤过程的分子途径和调控。在这 格兰特，我建议用多种方法来操纵肌动蛋白 细胞骨架，并确定肌动蛋白重塑如何促进UV- 诱导角质形成细胞凋亡。我将研究一下 明胶蛋白，一种钙激活的肌动蛋白细丝切断蛋白，它是 最近被确定为caspase-3的直接和主要底物， 在UVB介导的细胞凋亡中。这个项目是我的一个新方向 实验室，但非常适当和及时，因为很少是 已知肌动蛋白细胞骨架参与了细胞凋亡， 即使细胞骨架是一种重要的结构和调节 机器。它的混乱很可能会导致 许多皮肤病的病理生理学。我们有工具和 研究这个非常重要的基本生物学问题的专业知识， 并预计我们的发现将为 治疗/或预防许多皮肤病。

Apoptosis occurs under a variety of physiological and pathological conditions. It is essential for maintaining the homeostasis of the skin, and inappropriate apoptosis has been implicated in the pathogenesis of a multitude of skin disorders. Apoptosis mediates the decrease in cellularity during the transition between granulation to scar tissue, and aberrant apoptosis during wound healing has been attributed to the development of hypertrophic scars and keloids. Apoptosis may protect against the development of UV-induced skin cancer by selectively destroying sun-damaged keratinocytes. Mutations in the components of the surveillance machinery, such as p53 and bd-2, provide cells with an opportunity to escape from apoptosis and develop into nonmelanoma skin cancers. Early onset of apoptosis has been observed in diabetic wounds, contributing to blunted wound healing. Thus, manipulations which alter the onset or extent of apoptosis can potentially provide therapeutic interventions for the treatment of a variety of skin diseases. It is therefore important to delineate the molecular pathways and regulation of this multistep process. In this grant, I propose to use a variety of ways to manipulate the actin cytoskeleton and determine how actin remodeling contributes to UV- induced apoptosis in keratinocytes. I will examine the role of gelsolin, a Ca2+-activated actin filament severing protein which is recently identified as a direct and predominant substrate of caspase-3, in UVB-mediated apoptosis. This project is a new direction for my laboratory, but is very appropriate and timely because very little is known about the involvement of the actin cytoskeleton in apoptosis, even though the cytoskeleton is an important structural and regulatory machine. Its derangement is likely to contribute to the pathophysiological of many skin diseases. We have the tools and expertise to investigate this very important basic biological problem, and anticipate that our findings will suggest novel approaches for the treatment/or prevention of many skin diseases.