Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01

皮肤成体干细胞的协调细胞骨架动力学 - 重新提交 01

• 批准号: 8625508
• 负责人: Xiaoyang Wu
• 金额: $ 34.84万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625508
• 关键词: ATP phosphohydrolase; Actins; Adult; Animals; Binding; Binding Proteins; Cell Nucleus; Cell physiology; Cells; Collagen Type XVII; Complex; Crosslinker; Cytoskeletal Modeling; Cytoskeleton; Data; Defect; Development; Disease; Drug Targeting; F-Actin; Family; Genetic; Genetic Transcription; Glycogen Synthase Kinase 3; Hair; Hair follicle structure; Homeostasis; In Vitro; Injury; Investigation; Knock-out; Knockout Mice; Lead; Maintenance; Malignant Neoplasms; Mechanical Stress; Mediating; Microtubules; Molecular; Molecular and Cellular Biology; Motor; Mus; Natural regeneration; Organism; Pathway interactions; Phosphorylation; Play; Process; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Stem cells; Testing; Tissues; Wound Healing; base; cell behavior; combinatorial; crosslink; driving force; in vivo; late endosome; mouse model; mutant; new therapeutic target; novel therapeutics; paralogous gene; public health relevance; research study; response; self-renewal; skin disorder; tissue regeneration; trafficking; transmission process; wound

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.

项目摘要： Wnt信号在皮肤细胞的维持、激活和谱系定型中起着重要作用 干细胞（SSCs）。虽然越来越多的证据揭示了细胞骨架和运动蛋白的重要性， 在皮肤发育、组织稳态和创伤修复中， 传递小生境信号以调节皮肤SSCs中的Wnt通路。理解这个过程是 因为Wnt通路的缺陷会导致包括癌症在内的各种皮肤病。 在寻找参与这一过程的潜在细胞骨架调节因子时，我们发现， SPECTRAPLAKIN蛋白，ACF7（肌动蛋白交联因子7），在皮肤SSC中高度富集。我们的初步 结果揭示了ACF 7及其副产物BPAG 1（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。在本提案中，我们将 我们在皮肤SSCs方面的广泛专业知识的优势，以进行包括体内 ACF7和BPAG1突变动物的表征以及潜在的细胞和细胞因子的体外研究。 分子机制特别是，我们将测试一个中心假设，即细胞骨架动力学控制的 ACF7和BPAG1通过Wnt信号通路调节皮肤SSCs的功能。生成的数据 提出的实验将大大推进我们对皮肤SSC的基本机制的理解 行为。此外，我们的研究将可能导致新的治疗方法的发展， 与皮肤SSC相关的疾病。