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

基本信息

批准号：
9327655
负责人：
Xiaoyang Wu
金额：
$ 33.61万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/9327655
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 F-Actin Family Genetic Genetic Epistasis Genetic Transcription Glycogen Synthase Kinase 3 Hair Hair follicle structure Homeostasis Impairment 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 Self-control as a personality trait Signal Transduction Skin Skin Cancer Skin wound Stem cells Testing Tissues WNT Signaling Pathway Wound Healing base cell behavior combinatorial crosslink driving force experimental study in vivo late endosome molecular drug target mouse model mutant new therapeutic target novel therapeutics paralogous gene public health relevance response self-renewal skin disorder skin organogenesis tissue regeneration trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：Wnt信号在皮肤体细胞细胞（SSC）的维持，激活和谱系承诺中起关键作用。尽管积累的证据揭示了细胞骨架和运动蛋白在皮肤发育，组织稳态和伤口修复中的重要性，但尚不清楚细胞骨架动力学如何传递利基信号传导以调节皮肤SSC中的WNT途径。理解这一过程至关重要，因为WNT途径的缺陷导致包括癌症在内的各种皮肤疾病。在搜索此过程中涉及的潜在细胞骨架调节剂时，我们发现哺乳动物的光plaplakin蛋白ACF7（肌动蛋白交联因子7）高度富含皮肤SSC。我们的初步结果表明，ACF7及其旁系同源物BPAG1（大胆的烟碱抗原1）在协调细胞骨架动力学并在皮肤SSC中传输WNT信号。在此提案中，我们将利用我们在皮肤SSC中广泛专业知识的优势进行组合研究，其中包括ACF7和BPAG1突变动物体内表征的组合研究以及对基本细胞和分子机制的体外研究。特别是，我们将检验一个中心假设，即由ACF7和BPAG1控制的细胞骨架动力学通过Wnt信号通路调节皮肤SSC的功能。根据提出的实验产生的数据将大大提高我们对皮肤SSC行为基本机制的理解。此外，我们的研究将有可能导致与皮肤SSC相关疾病的新型治疗方法的发展。