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Understanding the mechanism of KSHV latent DNA replication

了解 KSHV 潜伏 DNA 复制机制

基本信息

批准号：
7471554
负责人：
Subhash C Verma
金额：
$ 12.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471554
关键词：
AT Rich Sequence Address Antibodies Autonomous Replication Biological Assay Biotechnology Bromodeoxyuridine Cell Cycle Cell Proliferation Cells Cloning Complex Consensus Sequence DNA DNA biosynthesis Deoxyuridine Doctor of Philosophy Elements Endothelial Cells Environment Episome Evaluation Family Geminin Gene Delivery Genes Genome Goals Graft Rejection HIV Health Human Human Herpesvirus 4 Human Herpesvirus 8 Immunoprecipitation Indium Individual Label Localized Malignant Neoplasms Maps Mediating Modeling Molecular Virology Nature Nucleotides Numbers Organ Transplantation Physiologic pulse Plasmids Postdoctoral Fellow Protein Dynamics Proteins Pulse taking Rate Replication Initiation Replication Origin Replicon Research Research Personnel Role Site Techniques Terminal Repeat Sequences Therapeutic Therapeutic immunosuppression Thymidine Transplant Recipients Viral Viral Proteins Virus Work analog career chromatin immunoprecipitation experience infected B cell inhibitor/antagonist latent infection member neoplastic cell prevent research study segregation single molecule tumor tumorigenesis vector viral DNA

项目摘要

DESCRIPTION (provided by applicant): Long-term goals: The overall goal of this project is to elucidate the replication mechanism of KSHV during latent infection. Kaposi's sarcoma associated Herpesvirus (KSHV) predominantly infects B cells and endothelial cells and persists indefinitely with the expression of a limited number of genes. These latent genes have been shown to induce cell proliferation/tumorigenesis. Viral DNA which persists as an episome gets passage to the dividing tumor cells during tumorigenesis. Although a number of studies have shown that TR region of the genome can support replication, the mechanism of the replication is not clearly understood. Studies elucidating the mechanism of latent DNA replication will provide clues of viral and cellular molecules required for replication initiation and therefore will allow targeting of these molecules as potential therapeutics. KSHV associated tumors is a major health problem for the HIV infected individuals as well as Organ transplanted patients undergoing immunosuppressive therapies to prevent graft rejections. Specific aims:1- Identification of the replication initiation sites on the KSHV genome and cloning of the KSHV regions capable of replicating and their replicative potential in Dpnl sensitivity assay. 2- Evaluation of the role of trans acting viral protein LANA on the replication of KSHV genome fragment. Meselson and Stahl experiment with the plasmids containing these replicating elements to determine the rate and nature (semi- conservative) of replication by these replicons. Evaluation for long-term persistence by these plasmids. 3- Determination of the cellular protein dynamics at the replication origins. The candidate has a Ph.D. in Biotechnology and almost four years of post-doctoral research experience in molecular virology working on KSHV encoded LANA and the replication of KSHV genome during latency. The immediate goal of the candidate is to understand the mechanism of KSHV latent DNA replication more specifically mapping of the LANA independent replication origin, sequence requirement and protein dynamics at replication initiation sites to specifically block KSHV mediated cancers. My long-term career goal is to establish myself as a independent researcher in a an academic environment in the field of molecular virology. This research will help to understand the replication and passage of virus in tumor cells and thereby using specific inhibitors replication and passage of the virus in the tumor cells will be blocked.

项目描述（由申请人提供）：长期目标：本项目总体目标是阐明潜伏感染期间KSHV的复制机制。卡波西肉瘤相关疱疹病毒（KSHV）主要感染B细胞和内皮细胞，并通过有限数量基因的表达无限期持续存在。这些潜伏基因已被证明可诱导细胞增殖/肿瘤发生。在肿瘤发生过程中，以片段形式存在的病毒DNA进入分裂的肿瘤细胞。虽然多项研究表明基因组的TR区可以支持复制，但其复制机制尚不清楚。阐明潜在DNA复制机制的研究将为复制起始所需的病毒和细胞分子提供线索，从而使这些分子成为潜在的治疗药物。KSHV相关肿瘤是HIV感染者以及接受免疫抑制治疗以防止移植排斥的器官移植患者的主要健康问题。