Import of Adenovirus DNA into the nucleus

将腺病毒 DNA 导入细胞核

• 批准号: 6988508
• 负责人: Larry R. Gerace
• 金额: $ 36.66万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988508
• 关键词: Import; Adenovirus; DNA; into; nucleus

DESCRIPTION (provided by applicant): Adenoviruses are non-enveloped DNA viruses with an -36 kb genome. In humans, adenoviruses cause a significant number of gastrointestinal and respiratory infections. They also are a major cause of viral conjunctivitis, including epidemic keratoconjunctivitis (EKC), a condition that can threaten long-term visual function and for which there is no effective treatment. In addition, adenoviruses are being intensively investigated as vectors for human gene therapy because of their broad tissue tropism. Although significant insight has been obtained on how adenovirus penetrates the cell to reach the cytoplasm, little is known about the molecular mechanism of nuclear import of the adenovirus genome, which is critical for virus reproduction. This proposal is directed at obtaining detailed molecular insight on adenovirus DNA import. The aims are: 1) The mechanism for docking of adenovirus to the nuclear pore complex will be investigated, focusing on an analysis of the adenovirus hexon protein and its interaction with specific nucleoporins. 2) The role of protein VII in the transport of adenovirus DNA through the nuclear pore complex will be analyzed, and the possibility that protein VII can be used as a nonviral method for achieving efficient gene transfer will be investigated. 3) The role of cytosolic factors, including hsc70 and its cofactors, in virus uncoating at the pore complex and in DNA import, will be analyzed. Considered together, this work will provide a valuable model for understanding the nuclear import of the genomes of pathogenic DNA viruses. The work also could potentiate the development of new therapies for EKC in humans. Finally, it could provide the basis for developing efficient means for nonviral gene transfer, which would be useful for gene therapy and functional studies of cells.

描述（由申请人提供）：腺病毒是具有-36 kb基因组的无包膜DNA病毒。在人类中，腺病毒引起大量胃肠道和呼吸道感染。它们也是病毒性结膜炎的主要原因，包括流行性角结膜炎 (EKC)，这种疾病可能威胁长期视觉功能，并且没有有效的治疗方法。此外，由于腺病毒具有广泛的组织趋向性，人们正在对腺病毒作为人类基因治疗的载体进行深入研究。尽管人们对腺病毒如何穿透细胞到达细胞质有了重要的了解，但对腺病毒基因组入核的分子机制知之甚少，而腺病毒基因组对病毒复制至关重要。该提案旨在获得有关腺病毒 DNA 导入的详细分子见解。目的是：1）研究腺病毒与核孔复合物对接的机制，重点分析腺病毒六邻体蛋白及其与特定核孔蛋白的相互作用。 2）分析蛋白VII在腺病毒DNA通过核孔复合体转运中的作用，并研究蛋白VII作为非病毒方法实现高效基因转移的可能性。 3) 将分析细胞质因子（包括 hsc70 及其辅助因子）在病毒在孔复合物脱壳和 DNA 输入中的作用。综合考虑，这项工作将为理解致病性 DNA 病毒基因组的核输入提供一个有价值的模型。这项工作还可以促进人类 EKC 新疗法的开发。最后，它可以为开发有效的非病毒基因转移手段提供基础，这将有助于基因治疗和细胞功能研究。