Characterizing genome-wide alternative splicing in HPV related HNSCC

HPV 相关 HNSCC 中全基因组选择性剪接的特征

基本信息

批准号：
8952460
负责人：
Daria A Gaykalova
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8952460
关键词：
Affect Alcohols Alternative Splicing Biological Assay Biological Markers Biology Characteristics DNA Sequence Alteration Data Detection Development Diagnosis Disease Down-Regulation Epigenetic Process Event Exons Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Future Genes Genetic Goals Grant HPV-High Risk Head and Neck Squamous Cell Carcinoma Head and neck structure Heterogeneity Human Papillomavirus Human papilloma virus infection Incidence Investigation Lead Liquid substance Malignant Neoplasms Malignant neoplasm of cervix uteri Mutation Normal tissue morphology Oncogenes Oncogenic Oropharyngeal Pathologic Pathway interactions Patients Pilot Projects Play Population Proto-Oncogene Proteins c-akt Public Health RNA Splicing Relative (related person)Role Sampling Solid Solid Neoplasm Staging Techniques The Cancer Genome Atlas Therapeutic Time Tobacco Transcript Transcription Alteration Tumor Suppressor Proteins United States Up-Regulation Validation Variant Woman cancer cell candidate validation cell transformation clinical application cohort design differential expression genome-wide genome-wide analysis high throughput analysis improved insight male men new therapeutic target non-smoking novel outcome forecast prognostic protein expression public health relevance response targeted treatment therapy development transcriptome sequencing tumor

项目摘要

DESCRIPTION (provided by applicant): The incidence of Human Papilloma Virus related to head and neck squamous cell carcinoma (HPV+ HNSCC) is rapidly increasing in the United States. HPV+ HNSCC has distinct etiologic, demographic, and clinico- pathologic characteristics in comparison to non-HPV related HNSCC. However, the therapy development for HPV+ HNSCC is challenging due to a low incidence of targetable oncogenic mutations and limited transcriptional characterization in comparison to other solid tumors. The investigation of alternative RNA splicing events (ASEs), provides insight into novel transcription alterations, and can expand the transcriptional characterization of HPV+ HNSCC. Our project will define HPV+ HNSCC specific alternative splicing events via two specific aims: (1) Definition of differential alternative splicing in primary HPV+ HNSCC, and (2) Validation of differential alternative splicing in HPV+ HNSCC. We will use outlier analysis in combination with high throughput analysis of transcriptional products to define high value ASEs specific for HPV+ HNSCC. We will perform validation of detected ASE candidates using multiple cohort and complementary validation techniques. This project will provide insight into HPV+ HNSCC biology and will potentially provide therapeutic and prognostic targets for the development of HPV+ HNSCC specific therapies. The data developed during the proposed R21 award will be used as preliminary data for an R01 grant, seeking to discover the functional role of splicing events and correlation of alternative splicing with patient clinicopathological parameters in order to develop the translational therapeutic and clinical application of targeting HPV+ HNSCC specific ASEs.

描述（由申请人提供）：与非头颈部鳞状细胞癌（HPV+ HNSCC）相关的人乳头瘤病毒的发病率在美国迅速增加，与非头颈鳞状细胞癌相比，HPV+ HNSCC 具有独特的病因学、人口统计学和临床病理学特征。 -HPV 相关的 HNSCC 然而，与其他疾病相比，HPV+ HNSCC 的治疗开发具有挑战性，因为可靶向致癌突变的发生率较低且转录特征有限。选择性 RNA 剪接事件 (ASE) 的研究提供了对新转录改变的深入了解，并且可以扩展 HPV+ HNSCC 的转录特征。我们的项目将通过两个具体目标定义 HPV+ HNSCC 特定的选择性剪接事件：(1) 定义。 (2) HPV+ HNSCC 中差异选择性剪接的验证，以及 (2) HPV+ HNSCC 中差异选择性剪接的验证我们将结合高通量分析使用离群值分析。我们将使用多个队列和补充验证技术对检测到的 ASE 候选物进行验证，以定义针对 HPV+ HNSCC 的高价值 ASE。 HPV+ HNSCC 特异性疗法。在拟议的 R21 资助期间开发的数据将用作 R01 资助的初步数据，旨在发现剪接事件的功能作用以及选择性剪接与患者的相关性。临床病理参数以开发针对 HPV+ HNSCC 特异性 ASE 的转化治疗和临床应用。