IGF-1 APOPTOTIC DEFENSES IN MELANOCYTES AND VITILIGO

白癜风影响着全球1%的人口。这种非常常见的皮肤病在美国和世界各地的黑皮肤人群中意义重大。在许多国家和社会，白癜风患者被视为弃儿。我们认为，黑素细胞对细胞死亡的防御在白癜风中被克服，在白癜风重新着色期间必须恢复。我们假设胰岛素样生长因子1(IGF-1)是黑素细胞功能的关键介质，通过维持抗凋亡防御来刺激黑素细胞的运动和增殖，并促进黑素细胞的存活。这项提议将定义黑素细胞的IGF-1抗凋亡防御机制。具体目标1将证明IGF-1维持人类黑素细胞对凋亡的抵抗力，并将决定哪些抗凋亡蛋白由IGF-1控制。具体目标2将确定这些IFG-1中的哪些作用是通过RAS信号通路介导的。特异性目标3将确定IGF-1依赖的抗凋亡防御是通过PI3K还是AKT/PBK介导的。具体目标4将确定整合素受体和IGF-1受体是否协同作用来控制黑素细胞的抗凋亡防御。这些项目具有创新性，因为它：i)。将细胞凋亡和细胞死亡的现代分子控制知识应用于黑素细胞存活的研究，黑素细胞存活是与人类白癜风相关的基本生物学特征，ii)关注IGF-1在黑素细胞生物学中的作用。IGF-1是黑素细胞功能的强大介质，在其他类型的细胞中调节关键的生存机制。这项RO拨款中提议的实验将为未来关于IGF-1作为白癜风生存因素的RO1提供初步数据。对IGF-1控制黑素细胞存活的详细机制的研究将为IGF-1在白癜风黑素细胞破坏中的相对作用以及白癜风再色素沉着过程中黑素细胞存活的问题提供适当的基础。

Vitiligo affects 1 percent of the population worldwide. This very common skin affliction is of great significance among dark skinned people in the United States and worldwide. In many countries and societies people with vitiligo are treated as outcasts. We propose that the defenses of melanocytes against cell death are overcome in vitiligo, and must be restored during vitiligo repigmentation. We hypothesize that Insulin-like Growth Factor 1 (IGF-1) is a critical mediator of melanocyte function, stimulating melanocyte movement and proliferation and promoting melanocyte survival by maintaining anti-apoptotic defenses. This proposal will define the IGF-1 anti-apoptotic defenses of melanocytes. Specific Aim 1 will demonstrate that IGF-1 maintains the resistance of human melanocytes to apoptosis and will determine which anti-apoptotic proteins are controlled by IGF-1. Specific Aim 2 will determine which of these IFG-1 effects are mediated through the Ras signaling pathway. Specific Aim 3 will determine whether IGF-1 dependent anti-apoptotic defenses are mediated through PI3K or AKT/PBK. Specific Aim 4 will determine whether intergrin receptors and the IGF-1 receptor act synergistically to control anti-apoptotic defenses in melanocytes. These project is innovative because it: i). Applies modern knowledge of the molecular control of apoptosis and cell death to the study of melanocyte survival, a fundamental biologic feature relevant to human vitiligo, and ii) focuses attention on the role of IGF-1 in melanocyte biology. IGF-1 is a powerful mediator of melanocyte function and mediates crucial survival mechanism in other types of cells. The experiments proposed in this RO3 grant will provide the preliminary data for a future RO1 on IGF-1 as a survival factor in vitiligo. The detailed mechanistic studies of IGF-1 control of melanocyte survival will provide a proper basis for questions concerning the relative role of IGF-1 in melanocyte destruction in vitiligo, and of melanocyte survival during repigmentation of vitiligo.