Shutoff of cellular gene expression by Kaposi's sarcoma-associated herpesvirus

卡波西肉瘤相关疱疹病毒关闭细胞基因表达

• 批准号: 7892365
• 负责人: Britt A Glaunsinger
• 金额: $ 10.39万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892365
• 关键词: AIDS with Kaposi' s sarcoma; Acquired Immunodeficiency Syndrome; Affect; African; Angiogenic Factor; Biochemistry; Biological Models; Biology; Biomedical Research; Cell physiology; Cells; Cessation of life; Clinical; Collaborations; Common Neoplasm; Complex; DNA; Degradation Pathway; Disease; Elderly; Elements; Employee Strikes; Endothelial Cells; Evaluation; Exonuclease; Faculty; Family; Fibrinogen; Future; Gene Expression; Genes; Growth Factor; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immunocompromised Host; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Institution; Kaposi Sarcoma; Knowledge; Lead; Lesion; Lymphoma; Lymphoproliferative Disorders; Lytic; Lytic Phase; Malignant Neoplasms; Maps; Mediating; Medical center; Messenger RNA; Modeling; Molecular Biology; Monitor; Multicentric Angiofollicular Lymphoid Hyperplasia; Oncogenic Viruses; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Production; Proteins; RNA; Research; Resistance; Role; Scientist; Shapes; Staging; Training; Transplant Recipients; Viral; Viral Genes; Viral Proteins; Virion; Virus; Virus Diseases; Virus Replication; base; cell growth; cell type; cytokine; design; effusion; gammaherpesvirus; histogenesis; immunosuppressed; in vitro Model; insight; lytic replication; mRNA Transcript Degradation; men; novel; pathogen; prevent; programs; research study; tumor; tumorigenesis; virology; virus episome maintenance

DESCRIPTION (provided by applicant): The candidate has extensive training in the field of cancer virology and plans to extend her expertise in the field of biochemistry over the next 1-2 years as a postdoctoral fellow before transitioning into an independent faculty position at a major research institution. There, she aspires to make significant contributions to the field of human tumor virology and continue as an active participant in the training of future scientists. The UCSF medical center is an outstanding facility for biomedical research; it attracts world-class seminar speakers and provides an excellent forum for interaction and collaboration with a large variety of scientists who are world leaders in molecular biology and virology. Kaposi's sarcoma (KS) is the most common malignancy associated with untreated human immunodeficiency virus infection and is caused by a novel human herpesvirus, termed KSHV. During lytic replication, the virus induces a robust shutoff of nearly all cellular gene expression. This host shutoff is mediated by a protein conserved across the herpesvirus family but which has acquired a novel mRNA degradation function specific to KSHV. This proposal aims to reveal the mechanisms by which this viral protein promotes global cellular mRNA turnover through evaluation of the contribution of cellular mRNA degradation pathways and proteins to the host shutoff phenotype. Intriguingly, a small number of cellular genes escapes this virus-induced degradation, indicating that these genes likely play a critical role in KSHV biology. The specific sequence elements that confer protection to these escapees will be mapped and the mechanism by which they confer resistance will be investigated. In addition, the requirement for these cellular genes in the KSHV lifecycle will be determined by monitoring the progress of virus infection in their absence. Finally, the ability of gammaherpesviruses closely related to KSHV to promote host shutoff will be examined to assess the importance of this phenotype in similar human and non-human pathogens. The experiments designed herein to reveal how a single KSHV-encoded protein shuts down expression of nearly all cellular genes will provide valuable insight into how infection by this human tumor virus can progress to malignancy, and hopefully give us new clues for preventing the disease. In addition, knowledge generated from this research may extend to other cancer-associated human herpesviruses and provide key insight into their complex biology.

描述（由申请人提供）：候选人在癌症病毒学领域进行了广泛的培训，并计划在未来1 - 2年内作为博士后研究员在生物化学领域扩展她在生物化学领域的专业知识，然后再过渡到主要研究机构的独立教职员工。在那里，她渴望为人类肿瘤病毒学领域做出重大贡献，并继续作为未来科学家培训的积极参与者。 UCSF医疗中心是生物医学研究的杰出设施；它吸引了世界一流的研讨会演讲者，并为与分子生物学和病毒学领域的世界领导者的互动和合作提供了一个很好的论坛。 Kaposi的肉瘤（KS）是与未经治疗的人类免疫缺陷病毒感染相关的最常见的恶性肿瘤，是由一种新型的人类疱疹病毒引起的，称为KSHV。在裂解复制过程中，该病毒几乎诱导了几乎所有细胞基因表达的牢固关闭。该宿主的关闭是由在疱疹病毒家族中保守的蛋白质介导的，但已获得了针对KSHV的新型mRNA降解功能。该建议旨在通过评估细胞mRNA降解途径和蛋白质对宿主关闭表型的贡献来揭示该病毒蛋白促进全局细胞mRNA转换的机制。有趣的是，少数细胞基因逃脱了这种病毒诱导的降解，表明这些基因可能在KSHV生物学中起关键作用。将绘制向这些逃生者提供保护的特定序列元素，并研究其赋予抵抗力的机制。此外，KSHV生命周期中这些细胞基因的需求将通过监测病毒感染的进展来确定。最后，将检查与KSHV促进宿主关闭的伽马病毒的能力，以评估这种表型在类似的人类和非人类病原体中的重要性。本文设计的实验旨在揭示单个KSHV编码的蛋白如何关闭几乎所有细胞基因的表达，将为这种人类肿瘤病毒感染如何发展为恶性肿瘤，并希望为我们提供预防该疾病的新线索。此外，这项研究产生的知识可能会扩展到其他与癌症相关的人类疱疹病毒，并为其复杂的生物学提供关键的见解。