Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01

项目总结： WNT信号在皮肤体细胞的维持、激活和谱系承诺中起关键作用 干细胞(SSC)。尽管越来越多的证据揭示了细胞骨架和马达蛋白的重要性 在皮肤发育、组织动态平衡和伤口修复中，细胞骨架动力学如何变化仍不清楚。 在皮肤SSCs中传递生态位信号来调节Wnt通路。理解这一过程是 这很重要，因为Wnt途径的缺陷会导致包括癌症在内的各种皮肤疾病。 在寻找参与这一过程的潜在细胞骨架调节因子的过程中，我们发现一种哺乳动物 SPECRAKIN蛋白ACF7(肌动蛋白交叉连接因子7)在皮肤SSCs中高度丰富。我们的预赛 结果显示ACF7及其类似的BPAG1(大疱性类天疱疮抗原1)在 协调细胞骨架动力学，并在皮肤SSCs中传递Wnt信号。在这项提案中，我们将采取 我们在皮肤SSCs方面的广泛专业知识的优势，可以进行包括活体内的组合研究 ACF7和BPAG1突变动物的特性及其潜在细胞和功能的体外研究 分子机制。特别是，我们将测试一个中心假设，即细胞骨架动力学由 ACF7和BPAG1通过Wnt信号通路调节皮肤SSCs的功能。生成的数据。 拟议的实验将极大地促进我们对皮肤SSC的基本机制的理解 行为。此外，我们的研究可能会导致开发新的治疗方法。 与皮肤干细胞相关的疾病。

Project Summary: Wnt signaling plays a critical role in maintenance, activation and lineage commitment of skin somatic stem cells (SSCs). Although accumulating evidence unveils the significance of cytoskeleton and motor proteins in skin development, tissue homeostasis and wound repair, it remains unclear how cytoskeletal dynamics transmit the niche signaling to regulate the Wnt pathway in skin SSCs. Understanding this process is of fundamental importance because defects in the Wnt pathway lead to various skin diseases including cancer. In searching for potential cytoskeletal regulators involved in this process, we found that a mammalian spectraplakin protein, ACF7 (Actin Crosslinking Factor 7), is highly enriched in skin SSCs. Our preliminary results revealed a critical function of ACF7 and its paralog BPAG1 (Bullous Pemphigoid Antigen 1) in coordinating cytoskeletal dynamics and transmitting the Wnt signals in skin SSCs. In this proposal, we will take the advantages of our extensive expertise in skin SSCs to perform a combinatorial study encompassing in vivo characterization of ACF7 and BPAG1 mutant animals and in vitro investigation of the underlying cellular and molecular mechanisms. In particular, we will test a central hypothesis that cytoskeletal dynamics controlled by ACF7 and BPAG1 regulate functions of skin SSCs via the Wnt signaling pathway. Data generated from the proposed experiments will greatly advance our understanding of the basic mechanisms underlying skin SSC behaviors. In addition, our study will potentially lead to the development of novel therapeutic treatments for diseases related to skin SSCs.