Chromatin structure maintenance and cancer

染色质结构维持与癌症

基本信息

批准号：
8606197
负责人：
Jianxin You
金额：
$ 31.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606197
关键词：
Applications Grants Architecture Binding Biological Biological Process Bromodomain C-terminal Carcinogens Carcinoma Cell Cycle Regulation Cell physiology Cells Chromatin Chromatin Structure Chromosomal translocation Complement Defect Dissociation Gene Mutation Goals Grant Hereditary Disease Higher Order Chromatin Structure Histones Human Human Genetics Human Herpesvirus 8 Human Papillomavirus Imaging Techniques In Situ In Vitro Infection Link Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Microscopy Molecular Molecular Conformation Molecular Probes Morphology Mutation Nucleosomes Nuts Oncogenes Oncogenic Oncogenic Viruses Optics Outcome Study Papillomavirus Physiological Play Protein Isoforms Proteins Resolution Role Technology Viral Viral Proteins Virus Work anti-cancer therapeutic antigen binding cell growth cellular imaging cofactor insight latency-associated nuclear antigen neoplastic novel optical imaging prevent protein protein interaction public health relevance receptor reconstruction research study scaffold tool tumorigenic virus genetics

项目摘要

DESCRIPTION (provided by applicant): Chromatin structure organization is crucial for regulating many fundamental cellular processes. Perturbations of chromatin structure have been linked to many human genetic diseases including cancer. However the molecular mechanism that regulates the assembly of higher-order chromatin structure remains poorly understood. Our previous work identified the cellular protein Brd4 (bromodomain-containing protein 4) as a novel chromatin receptor for cervical cancer-associated papillomaviruses. Brd4 plays an important role in cell cycle regulation and cancer. Our functional studies have established the Brd4 function in chromatin structure maintenance. Brd4 is also a target of the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), and the genetic translocation t(15;19) that defines a highly lethal carcinoma. We hypothesize that abrogation of the Brd4 cellular function in chromatin structure maintenance underlies the oncogenic mechanisms for the tumorigenic viruses- and translocation-associated carcinoma. Our proposed studies will apply recently developed Stochastic Optical Reconstruction Microscopy (STORM) technology and in situ single cell imaging to further examine Brd4 function in chromatin structure organization. We will investigate the mechanisms by which Brd4 mediates the chromatin structure maintenance. Using the cancer-associated viral proteins and genetic mutations as molecular probes, we will further explore the mechanisms by which these oncogenic agents abrogate the Brd4 function to contribute to malignant progression. These integrated studies will provide greater understanding of the Brd4 function in higher-order chromatin organization and cancer. This study will present a paradigm for investigating the molecular mechanisms of other bromodomain- containing chromatin adaptors. The outcome of this study will offer promising leads for developing efficient anti-cancer therapeutic strategies.

描述（由申请人提供）：染色质结构组织对于调节许多基本细胞过程至关重要。染色质结构的扰动与包括癌症在内的许多人类遗传疾病有关。然而，调节高级染色质结构组装的分子机制仍然知之甚少。我们之前的工作将细胞蛋白 Brd4（含溴结构域蛋白 4）确定为宫颈癌相关乳头瘤病毒的新型染色质受体。 Brd4 在细胞周期调节和癌症中发挥着重要作用。我们的功能研究已经确定了 Brd4 在染色质结构维护中的功能。 Brd4 也是致癌卡波西肉瘤相关疱疹病毒 (KSHV) 和定义高致死性癌症的基因易位 t(15;19) 的靶标。我们假设 Brd4 在染色质结构维持中的细胞功能的废除是致瘤病毒和易位相关癌症的致癌机制的基础。我们提出的研究将应用最近开发的随机光学重建显微镜（STORM）技术和原位单细胞成像来进一步检查 Brd4 在染色质结构组织中的功能。我们将研究 Brd4 介导染色质结构维持的机制。使用与癌症相关的病毒蛋白和基因突变作为分子探针，我们将进一步探索这些致癌剂消除 Brd4 功能从而导致恶性进展的机制。这些综合研究将有助于更好地了解 Brd4 在高级染色质组织和癌症中的功能。这项研究将为研究其他含溴结构域的染色质接头的分子机制提供一个范例。这项研究的结果将为开发有效的抗癌治疗策略提供有希望的线索。