PHENOTYPE AND FUNCTION OF SENESCENT KERATINOCYTES

描述：（逐字逐句）-增强寿命的一种表现， 美国人是各种类型的皮肤癌的数量增加， 在皮肤中的细胞类型的积累，可能是接近年底， 复制潜力而表皮角质形成细胞和真皮 已经在老年个体中鉴定出成纤维细胞， 与衰老相关，衰老细胞在 皮肤的老化或肿瘤发生是未知的。而 关于衰老的成纤维细胞已经有了相当多的知识， 使用衰老的表皮角质形成细胞已经取得了进展 被视为一个动态的过程，而不是一个静态的条件，这些皮肤衍生 细胞类型。我们的假设是，衰老的角质形成细胞发挥重要作用， 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 从表型的角度，包括功能研究。初步数据显示 独特的分子变化，如细胞周期抑制剂的诱导 p16蛋白在衰老角质形成细胞中的表达，以及衰老角质形成细胞 角化细胞的增殖以抑制恶性细胞类型的增殖。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， 衰老，这一领域的快速发展将是可能的。体外和 体内试验将用于表征表型和功能 角质细胞的衰老。通过成功完成拟议目标， 将出现新的治疗策略以靶向癌前角质形成细胞， 以及先前存在的皮肤恶性肿瘤。由于许多肿瘤细胞绕过 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，可以应用于 恶性细胞通过恢复衰老途径导致不可逆的 生长停滞

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.