Chromatin structure maintenance and cancer

染色质结构维持与癌症

基本信息

批准号：
8225375
负责人：
Jianxin You
金额：
$ 32.2万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225375
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. PUBLIC HEALTH RELEVANCE: We have previously identified the bromodomain protein Brd4 as a host receptor for human papillomaviruses that are strongly associated with cervical cancer. In this grant, we propose to investigate the molecular mechanisms underlying the Brd4 function in chromatin structure maintenance. We will determine how abrogation of Brd4 cellular function by tumor viruses and genetic mutation could cause human cancers. This study will provide new insights 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，调节高阶染色质结构组装的分子机制仍然很少了解。我们以前的工作将细胞蛋白BRD4（含溴脱域的蛋白4）确定为与宫颈癌相关蛋白酶病毒的新型染色质受体。 BRD4在细胞周期调节和癌症中起重要作用。我们的功能研究已经在染色质结构维持中建立了BRD4功能。 BRD4也是致癌性Kaposi肉瘤相关的疱疹病毒（KSHV）的靶标，而遗传易位T（15; 19）定义了高度致命的癌。我们假设在染色质结构维持中，BRD4细胞功能的废除是肿瘤病毒和易位相关癌的致癌机制的基础。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，以进一步检查染色质结构组织中的BRD4功能。我们将研究BRD4介导染色质结构维持的机制。我们将使用癌症相关的病毒蛋白和遗传突变作为分子探针，我们将进一步探索这些致癌剂消除BRD4功能以导致恶性进展的机制。这些综合研究将对高阶染色质组织和癌症中的BRD4功能有更深入的了解。这项研究将提出一个范式，用于研究其他含有溴d的染色质衔接子的分子机制。这项研究的结果将为发展有效的抗癌治疗策略提供有希望的线索。公共卫生相关性：我们以前已将溴结构域蛋白BRD4确定为与宫颈癌密切相关的人乳头瘤病毒的宿主受体。在这笔赠款中，我们建议研究染色质结构维持中BRD4功能的分子机制。我们将确定如何通过肿瘤病毒废除BRD4细胞功能和遗传突变会导致人类癌症。这项研究将为开发有效的抗癌治疗策略提供新的见解。