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.

腺病毒是很有希望用于人类治疗的载体。引人注目的