Adenovirus-host interactions and in vivo virus targeting

腺病毒-宿主相互作用和体内病毒靶向

基本信息

批准号：
8267055
负责人：
Dmitry Shayakhmetov
金额：
$ 41.29万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8267055
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&apos 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

项目摘要

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.

腺病毒是用于人类治疗应用的有前途的载体。引人注目的 Ad 突变体的深刻表型之间存在差异，具有修饰单个衣壳蛋白，以及我们无法选择性地靶向肿瘤细胞血管内病毒传递强调了人们对病毒的冗余和重叠知之甚少当病毒通过血管内传递时，分子途径就会参与进来路线。该提案旨在进行全面的机制研究来定义 Ad衣壳的每个主要结构元件在介导病毒中的贡献与体内肝细胞的相互作用。使用大量先前构建的衣壳修改Ad向量后，我们将分析1）纤维结构的作用； 2）五邻体宿主整合素相互作用； 3) 六邻体-血液因子在介导广告捕获中的相互作用在血管内Ad递送后的肝脏和肝细胞转导中。基于积累的数据我们将4）构建肺癌细胞靶向溶瘤Ad载体逃脱肝脏的捕获并在小鼠模型中评估其抗肿瘤功效。这些研究将极大地提高我们对控制机制的理解 Ad-host 体内相互作用，最终将导致临床上有用的药物的开发用于治疗局部和播散性转移性肿瘤的靶向广告载体疾病。