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了对哺乳动物健康至关重要的最外层皮肤屏障表皮细胞中涉及 NF-κB、AP1 和 c-Myc 基因调节因子的细胞信号传导失调。可能导致局部和全身疾病以及癌症，然而，直接针对这些核心。转录因子已被证明在技术上具有挑战性，阻碍了有意义的临床转化。长期目标是探索 K63-泛素 (K63-Ub) 介导的信号如何汇聚到基因调控上并可以合理地靶向治疗炎症和肿瘤性皮肤病。最近的功能集中于表征 CYLD 的新成果，CYLD 是一种 K63-Ub 蛋白酶，其丢失- 功能与免疫疾病、不孕症、良性和恶性肿瘤有关。人类的 Cyld 会导致 Cyldm 综合征，其特征是广泛且反复出现的表皮和对于附件肿瘤，由于缺乏临床相关的研究，理解 CYLD 的完整作用受到阻碍。为了揭示新的疾病机制，我们建立了一个概括性的小鼠模型。利用该动物模型，我们鉴定了人类 Cyldm 综合征的遗传和表型特征。作为一种新的 CYLD 底物，UBE2N 作为 c-Myc 和雄激素信号传导的上游调节剂，此外 CYLD 在 NF-κB 和 AP1 通路调节中的作用这些发现强调了 CYLD 的广泛影响。 CYLD 和 Cyldm 皮肤模型的实用性可增强我们对新疾病机制的理解。本研究是基于上皮细胞中 UBE2N 功能不受阻碍的假设而设计的促进炎症和 c-Myc 依赖性皮肤缺陷。我们提出三个具体目标：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。利用小鼠和人类皮肤组织模型以及基因编辑的尖端技术，转录组和蛋白质相互作用组分析的完成将揭示新的分子。表皮形态发生的机制，并为皮肤炎症和癌症提供治疗见解。