PHENOTYPE AND FUNCTION OF SENESCENT KERATINOCYTES

描述：(逐字)-长寿能力增强的表现之一 美国人患各种皮肤癌的人数在增加，而 皮肤中细胞类型的堆积可能接近其生长的末端 复制潜力。而表皮角质形成细胞和真皮 已在老年个体中发现了表达标志物的成纤维细胞 与衰老相关的衰老细胞的生物学意义 皮肤是未知的，无论是关于衰老还是肿瘤发生。而当 关于衰老的成纤维细胞，已经出现了相当多的知识，更少的是 利用衰老表皮角质形成细胞可以实现衰老的研究进展 被认为是一个动态的过程，而不是一个静态的条件，这些皮肤衍生 单元类型。我们的假设是衰老的角质形成细胞扮演着重要的角色。 以自分泌和旁分泌的方式抑制肿瘤的发生 皮肤。我们建议进行一系列系统的实验，以确定 衰老角质形成细胞的分子属性，并超越这一点 表型视角包括功能研究。初步数据显示 独特的分子变化，如细胞周期抑制物的诱导 衰老角质形成细胞中p16蛋白的表达及其对衰老的影响 角质形成细胞可抑制各类恶性细胞的增殖。现在我们 已经发现了几种不同的触发衰老表型的方法 在角质形成细胞中，可以重复地切换以模拟复制 老龄化，这一领域的快速发展将是可能的。无论是体外培养还是 体内试验将被用来表征表型和功能 衰老的角质形成细胞。通过成功地完成所提议的目标， 针对癌前角质形成细胞的新治疗策略将会出现， 以及先前存在的皮肤恶性肿瘤。由于许多肿瘤细胞绕过了 衰老途径，关于衰老的分子基础的知识 衰老在正常角质形成细胞中被触发，可应用于 通过重建导致不可逆的衰老途径的恶性细胞 增长停滞。

DESCRIPTION: (Verbatim) - One manifestation of the enhanced longevity of Americans is the increased number of various types of skin cancers, and the accumulation of cell types in the skin that may be approaching the end of their replicative potential. While both epidermal keratinocytes and dermal fibroblasts have been identified in elderly individuals that express markers associated with senescence, the biological significance of senescent cells in skin is unknown, either with respect to aging or tumorigenesis. While considerable knowledge has emerged regarding senescent fibroblasts, much less progress has been made using senescent epidermal keratinocyte Senescence can be regarded as a dynamic process and not a static condition for these skin-derived cell types. Our hypothesis is that senescent keratinocytes play important roles both in an autocrine and paracrine fashion to suppress tumorigenesis in the skin. We propose to perform a systematic series of experiments to define the molecular attributes of senescent keratinocytes, and move beyond this phenotypic perspective to include functional studies. Preliminary data indicate distinctive molecular changes such as induction of the cell cycle inhibitor protein p16 in senescent keratinocytes, as well as the ability of senescent keratinocytes to inhibit proliferation of malignant cell types. Now that we have uncovered several different methods for triggering the senescent phenotype in keratinocytes that can be reproducibly switched to simulate replicative senescence, rapid progress in this field will be possible. Both in-vitro and in-vivo assays will be utilized to characterize the phenotype and function of senescent keratinocytes. By successfully completing the proposed objectives, new therapeutic strategies will emerge to target pre-malignant keratinocytes, as well as pre-existing cutaneous malignancies. Since many tumor cells bypass the senescent pathway, knowledge gained about the molecular basis by which senescence is triggered in normal keratinocytes, could be applied to the malignant cells by re-instating the senescent pathway leading to irreversible growth arrest.