Novel Genetic Models to Study the Role of DNp63 in Squamous Cell Carcinoma

研究 DNp63 在鳞状细胞癌中作用的新遗传模型

基本信息

批准号：
8585388
负责人：
Rose-Anne Romano
金额：
$ 7.95万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2013-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8585388
关键词：
Address Alleles Animals Apoptotic Area Biological Markers Biological Models Cell Aging Cell Survival Cervical Coupled Critical Pathways Data Development Diagnostic Neoplasm Staging Disease Disease Progression Epigenetic Process Epithelial Esophageal Etiology Event Future Gene Targeting Genes Genetic Genetic Models Glean Goals Head Head and Neck Squamous Cell Carcinoma Human Incidence Investigation Knock-in Mouse Knockout Mice Knowledge Laboratories Large-Scale Sequencing Lung Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Mus Neoplasm Metastasis Oncogenes Oncogenic Pathogenesis Pathway interactions Phenotype Play Prevalence Prognostic Marker Property Prostate Protein Isoforms Proteins Protocols documentation Public Health Regulator Genes Reporting Research Role Signal Pathway Signal Transduction Skin Skin Cancer Skin Carcinogenesis Squamous Cell Neoplasms Squamous cell carcinoma Staging The Cancer Genome Atlas Therapeutic Transgenic Mice Tumor Suppressor Proteins Tumor stage Work base chemical carcinogenesis chromatin immunoprecipitation deep sequencing effective therapy gain of function genome-wide in vivo innovation insight interest loss of function mouse model novel novel diagnostics overexpression public health relevance research study skin disorder transcription factor tumor tumor initiation tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Squamous cell carcinoma (SCC) is one of the most common forms of skin malignancies with increasing global incidence, thus constituting a serious public health concern. Although to date the underlying genetic and epigenetic events contributing to the development and progression of SCC have been intensively studied, no resulting preventative or therapeutic strategies have been successfully developed to target this potentially lethal form of skin cancer. Therefore there is a vital need for additional studies to better understand the molecular etiology of this skin disease and harness that knowledge for the development of new and effective treatments. Evidence from our laboratory as well as others, together with the large-scale sequencing data emerging from the Cancer Genome Atlas Project, strongly suggest that the transcription factor p63, specifically the most prevalent Np63 isoforms, function as an oncogene in the early stages of SCC development. We show that overexpression of Np63 in transgenic mouse (Np63BG) skin results in a severe phenotype that share many of the underlying histological, pathological and molecular features associated with the early stages of SCC. However, our current knowledge regarding the molecular underpinnings through which Np63 functions in the early stages of SCC remains sparse. Hence, we will utilize Np63BG and Np63-GFP knock- in mice, both of which were developed in our laboratory, to address two important areas of interest. First, given the elevated levels of Np63 in SCC, we propose to experimentally evaluate the contribution of this isoform in the early stages of tumor development by performing two-stage skin chemical carcinogenesis studies on the Np63BG and Np63 heterozygous mice. Data obtained from such in vivo studies will establish the oncogenic function of Np63 and provide a better understanding of the specific role of the Np63 isoforms in the early stages of SCC initiation and progression, which to date have not been possible due to the lack of Np63 isoform specific mouse models. Secondly we propose to identify, on a genome-wide scale, Np63 specific target genes and regulatory networks contributing to the development of SCC. Towards this end, we will perform chromatin-immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) to identify novel direct target genes of Np63, which are altered in the Np63BG mouse skin, and which likely contribute to the development of SCC. Collectively the information gleaned from these genetic studies has the potential to not only significantly enhance our molecular understanding of the underlying pathogenic alterations of SCC but also to unearth new driver pathways and critical players for future exploitation as therapeutic options.

描述（由申请人提供）：鳞状细胞癌（SCC）是最常见的皮肤恶性肿瘤形式之一，全球发病率增加，因此构成了严重的公共健康问题。尽管已经深入研究了迄今为止有助于SCC发展和进展的基本遗传和表观遗传事件，但尚未成功开发出尚未成功地针对这种潜在的致命性皮肤癌。因此，至关重要的是进行其他研究，以更好地了解这种皮肤疾病的分子病因和利用这一知识，以发展新的有效疗法。我们实验室和其他实验室的证据，以及来自癌症基因组图集项目的大规模测序数据，强烈表明转录因子p63，特别是最普遍的NP63同工型，在SCC开发早期阶段起癌素的作用。我们表明，转基因小鼠（NP63BG）皮肤中NP63的过表达导致严重的表型，具有许多与SCC早期阶段相关的基本组织，病理和分子特征。但是，我们目前关于NP63在SCC早期起作用的分子基础知识仍然很少。因此，我们将在小鼠中利用NP63BG和NP63-GFP敲击，这两者都是在我们的实验室中开发的，以解决两个重要领域。首先，鉴于SCC中NP63的水平升高，我们建议通过对NP63BG和NP63杂合小鼠进行两级皮肤化学癌变研究，从而在肿瘤发育的早期进行实验评估该同工型的贡献。从这种体内研究获得的数据将建立NP63的致癌功能，并更好地理解NP63同工型在SCC启动和进展的早期阶段的特定作用，迄今为止由于缺乏NP63同工型特异性小鼠模型而无法实现。其次，我们建议在全基因组量表上鉴定NP63特定靶基因和有助于SCC发展的调节网络。为此，我们将执行染色质 - 免疫沉淀（芯片），然后进行深层测序（CHIP-SEQ），以识别NP63的新型直接靶基因，这些靶基因在NP63BG小鼠皮肤中会改变，并可能有助于SCC的发展。从这些遗传研究中收集的信息总体上不仅可以显着增强我们对SCC潜在的致病性改变的分子理解，还可以发掘新的驱动程序途径和关键参与者，以将来的剥削作为治疗选择。