Adenovirus-host interactions and in vivo virus targeting

腺病毒-宿主相互作用和体内病毒靶向

• 批准号: 8468662
• 负责人: Dmitry Shayakhmetov
• 金额: $ 37.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468662
• 关键词: Ablation; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Affect; Affinity; Amino Acid Sequence; Amino Acids; Area; Binding; Binding Sites; Biology; Blood; Blood Cells; Blood Circulation; Blood Coagulation Factor; Blood Platelets; Capsid; Capsid Proteins; Cell Communication; Cell surface; Cells; Clinical Research; Clinical Trials; Coagulation Process; Collaborations; Complex; Cryoelectron Microscopy; DNA; Data; Deposition; Development; Discontinuous Capillary; Disease; Dose; Elements; Employee Strikes; Endosomes; Endothelial Cells; Factor Analysis; Factor IX; Fiber; Gene Delivery; Gene Transfer; Generations; Goals; Hepatic Tissue; Hepatocyte; Hepatotoxicity; Histocompatibility Testing; Human; Human Adenoviruses; Human Genetics; Immune response; In Vitro; Individual; Infection; Infectious Agent; Inflammatory; Integrins; Intravenous; Investigation; Knowledge; Kupffer Cells; Lead; Life; Liver; Local Therapy; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Minor; Modeling; Modification; Molecular; Mutate; Mutation; Neoplasm Metastasis; Oncolytic; Pathway interactions; Peptides; Phenotype; Protein Binding; Proteins; RGD (sequence); Research; Resolution; Risk; Role; Route; Safety; Saturn' s Moon Phoebe; Series; Serotyping; Structure; Surface Plasmon Resonance; Therapeutic; Therapeutic Intervention; Tissues; Tropism; Universities; Vaccination; Variant; Viral; Viral Vector; Virus; Virus Diseases; adenovirus penton protein; adenovirus receptor; anti-cancer therapeutic; base; cell type; cellular transduction; clinical application; clinically significant; defined contribution; flexibility; gene delivery system; improved; in vivo; lung Carcinoma; monocyte; mouse model; mutant; neoplastic cell; novel; particle; penton base; prevent; therapeutic gene; transgene expression; tumor; tumor-selective adenovirus; vector; virus host interaction

Adenoviruses are promising vectors for therapeutic applications in humans. The striking discrepancy between profound phenotypes of Ad mutants, possessing modifications in individual capsid proteins, and our inability to selectively target tumor cells after intravascular virus delivery underscores poorly appreciated redundancy and overlap of molecular pathways, which become engaged when virus is delivered via intravascular route. This proposal is to conduct comprehensive mechanistic studies to define the contribution of each of the major structural elements of the Ad capsid in mediating virus interaction with liver cells in vivo. Using a large set of previously constructed capsid- modified Ad vectors, we will analyze the role of 1) the fiber structure; 2) the penton-host integrin interactions; and 3) the hexon-blood factor interactions in mediating Ad trapping in the liver and hepatocyte transduction after intravascular Ad delivery. Based on the accumulated data we will 4) construct a lung carcinoma cell-targeted oncolytic Ad vector that escapes trapping by the liver and evaluate its anti-tumor efficacy in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and will ultimately lead to the development of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.

腺病毒是一种很有希望用于人类治疗的载体。那次罢工 Ad突变体的深刻表型之间的差异，在 单个衣壳蛋白，以及我们在治疗后无法选择性地靶向肿瘤细胞 血管内病毒传递强调缺乏认识的冗余和重叠 当病毒通过血管内传播时，参与的分子途径 路线。这项建议是进行全面的机制研究，以界定 腺病毒衣壳蛋白各主要结构元件在介导病毒中的作用 体内与肝细胞的相互作用。使用一大套先前建造的衣壳- 修饰的Ad载体，我们将分析1)纤维结构的作用；2)五元主机的作用 整合素相互作用；3)六邻体-血液因子相互作用在介导广告捕获中的作用 血管内注射Ad后在肝脏和肝细胞内的转导。基于 积累数据4)构建靶向肺癌细胞的溶瘤Ad载体 这种药物可以逃脱肝脏的捕获，并在小鼠模型中评估其抗肿瘤效果。 这些研究将极大地提高我们对治理机制的理解 体内的腺病毒与宿主的相互作用最终将导致临床有用的发展 靶向性腺病毒载体治疗局部和播散性转移瘤 疾病。