K63-Ubiquitin-mediated cell signal regulation in epidermis

K63-泛素介导的表皮细胞信号调节

基本信息

批准号：
9903230
负责人：
Jennifer Yunyan Zhang
金额：
$ 35.42万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903230
关键词：
Acne Androgen Receptor Androgens Animal Model Apoptosis Benign Cells Chemicals Clinic Clustered Regularly Interspaced Short Palindromic Repeats Coenzyme A Coenzymes Crohn&apos s disease DNA Repair Data Defect Disease Disease model Dominant Genetic Conditions Enzymes Epidermis Epithelial Cells Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Diseases Goals Growth Hair Hair follicle structure Hand Health Homeostasis Human Hyperplasia Immune System Diseases Infertility Inflammation Inflammatory Lead Link Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Methods Modeling Molecular Morphogenesis Mus Nature Nuclear Oncogenes Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Peptide Hydrolases Pharmacology Phenotype Play Post-Translational Protein Processing Process Proteins Proteomics Protocols documentation Psoriasis Receptor Inhibition Recurrence Regulation Regulator Genes Role SHH gene Sebaceous Glands Sebaceous adenoma Signal Transduction Site Skin Skin Appendage Neoplasm Skin Cancer Skin Carcinogenesis Skin Tissue Syndrome Technology Therapeutic Tissue Model Tissues Transcription Factor AP-1 Translations Tumor Suppression Ubiquitin Ubiquitination Work appendage base c-myc Genes clinical effect clinical translation clinically relevant cofactor design dimethylbenzanthracene epidermal stem cell human disease immune function inhibitor/antagonist insight keratinocyte loss of function male fertility mouse model mutant neoplastic novel receptor expression skin barrier skin disorder skin regeneration small hairpin RNA stem cell differentiation stem cells targeted treatment therapy development transcription factor transcriptome tumor tumor growth tumorigenesis

项目摘要

ABSTRACT Epidermis and its appendages constitute the outermost skin barrier essential for mammalian health and survival. Dysregulation of cell signaling in epidermal cells involving NF-κB, AP1, and c-Myc gene regulators can lead to local and systemic disorders, as well as cancer. Nevertheless, direct targeting of these core transcription factors has been proven technically challenging, prohibiting a meaningful clinical translation. Our long-term objective is to explore how K63-Ubiquitin (K63-Ub)-mediated signals converge on gene regulation and can be rationally targeted for therapy of inflammatory and neoplastic skin disorders. Towards this end, our recent efforts are focused on characterizing novel functions of CYLD, a K63-Ub protease whose loss-of- function is linked to immunological diseases, infertility, and benign and malignant neoplasms. While mutant Cyld in humans leads to Cyldm-syndrome characterized by widespread and recurrent epidermal and appendage tumors, understanding the complete role of CYLD is hampered by the lack of a clinically relevant disease model. To uncover novel disease mechanisms we have generated a mouse model that recapitulates genetic and phenotypic features of human Cyldm-syndrome. Using this animal model, we have identified c-Myc as a new CYLD substrate, UBE2N as an upstream regulator of c-Myc and androgen signaling, in addition to a role of CYLD in the regulation of the NF-κB and AP1 pathways. These findings highlight the broad impact of CYLD and the utility of the Cyldm skin model for increasing our understanding of novel disease mechanisms. This study is designed based on the hypothesis that unopposed UBE2N function in epithelial cells promotes inflammation and c-Myc-dependent skin defects. We propose three specific aims: 1) to define the role of c-Myc in Cyldm skin; 2) to determine the molecular mechanisms underlying K63-Ub-mediated c-Myc activation; and 3) to determine the functions of UBE2N in epidermal proliferation and tumorigenesis. We will utilize mouse and human skin tissue models, as well as cutting-edge technologies for gene editing, transcriptome and protein interactome analyses. Completion of these studies will reveal novel molecular mechanisms of epidermal morphogenesis and provide therapeutic insights for skin inflammation and cancer.

抽象的表皮及其附属物构成对哺乳动物健康至关重要的皮肤屏障生存。涉及NF-κB，AP1和C-MYC基因调节剂的表皮细胞中细胞信号的失调可以导致局部和全身性疾病以及癌症。但是，直接针对这些核心转录因子在技术上具有挑战性，禁止有意义的临床翻译。我们的长期目标是探索K63-泛素（K63-UB）介导的信号如何在基因调节上汇聚并且可以理性地用于治疗炎症性和肿瘤性皮肤疾病。为此，我们的最近的努力集中在表征CYLD的新功能，CYLD是一种K63-UB蛋白酶，其丧失损失功能与免疫疾病，不育症以及良性和恶性肿瘤有关。而突变体人类中的Cyld导致Cyldm Syndrome，其特征是宽度和经常性表皮和缺乏临床相关的附属物肿瘤，了解CYLD的完整作用受到阻碍疾病模型。为了揭示新的疾病机制，我们已经生成了一个概括的小鼠模型人cyldm综合征的遗传和表型特征。使用这种动物模型，我们已经确定了C-MYC 作为新的CYLD底物，UBE2N作为C-Myc和雄激素信号的上游调节剂，此外 CYLD在NF-κB和AP1途径的调节中的作用。这些发现突出了 CYLD和CYLDM皮肤模型的实用性，以增加我们对新型疾病机制的理解。这项研究的设计基于上皮细胞中无反对的UBE2N功能的假设促进感染和C-MYC依赖性皮肤缺陷。我们提出了三个具体目标：1）定义 C-Myc在CyLdm皮肤中的作用； 2）确定K63-UB介导的C-MYC的分子机制激活; 3）确定UBE2N在表皮增殖和肿瘤发生中的功能。我们将利用小鼠和人类皮肤组织模型，以及用于基因编辑的尖端技术，转录组和蛋白质相互作用组分析。这些研究的完成将揭示新的分子表皮形态发生的机制，并为皮肤感染和癌症提供治疗见解。