Ad5 Fiber and Penton mts: Influence on immune activation

Ad5 Fiber 和 Penton mts：对免疫激活的影响

• 批准号: 7146705
• 负责人: ERIK S FALCK-PEDERSEN
• 金额: $ 39.82万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146705
• 关键词: Address; Adenoviruses; Antigen-Presenting Cells; Antigens; Antiviral Agents; Antiviral Response; Binding; Biological Assay; Biology; Bone Marrow; CD14 gene; Capsid; Capsid Proteins; Cell Line; Cell Maturation; Cells; Characteristics; Coculture Techniques; Complement; Data; Dendritic Cells; Dendritic cell activation; Dose; Elements; Epitopes; Event; Exposure to; Fiber; Gene Transduction Agent; Gene Transfer; Genes; Genetic; Genetic Transcription; Hepatotoxicity; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Integrins; Kinetics; Knowledge; Laboratories; Light; Macrophage Activation; Mediating; Modification; Molecular; Mus; Mutate; Nature; Pathway interactions; Phase; Process; RGD (sequence); Recombinants; Research Personnel; Staging; Stem cells; T-Cell Proliferation; T-Lymphocyte; TNF gene; Technology; Testing; Time; Transduction Gene; Viral; Viral Vector; Virus; Virus Activation; Virus Diseases; adenovirus penton protein; autocrine; base; cell type; cytokine; cytotoxicity; gene replacement; in vivo; insight; interest; macrophage; mutant; research study; response; vector

DESCRIPTION (provided by applicant): Our laboratory has had a long-standing interest in the biology of Adenovirus, Ad vectors and how Ad capsid proteins contribute to gene transduction and immune activation. The current proposal addresses the question of how the immune system recognizes a virus at the earliest stages of the host response to infection. The knowledge gained from the proposed studies will allow us to generate new viral vectors that have "stealth" characteristics, and at the same time, will highlight the mechanisms normally resulting in robust inflammation and immunity against wild type Ad. Stealth vectors will allow safer gene transfer and more prolonged expression of transferred genes. The proposed studies are based on a new hypothesis arising from our preliminary data: That two of the major types of antigen presenting cells (APCs)-dendritic cells (DC) and macrophages (MO)-regulate the nature and magnitude of the host immune response to Ad; that APC's detect the virus through a restricted subset of Ad's potential antigens and epitopes; that the dominant epitopes reside in capsid proteins, yet are different for the two types of APC; that the dominant epitope for DC resides in the penton capsid protein; and that the dominant epitope for MO resides in the fiber capsid protein. We have constructed a new set of Ad vectors mutated in penton and fiber that will allow us to test this hypothesis. The results of these studies will not only hold practical implications for gene transfer applications, but will shed new light on fundamental aspects of the earliest phases of viral recognition by the immune system.

描述（由申请人提供）： 我们的实验室对腺病毒，AD载体的生物学以及AD CAPSID蛋白如何对基因转导和免疫激活有贡献有很长的兴趣。当前的提案解决了免疫系统如何在宿主对感染反应的最早阶段识别病毒的问题。从拟议的研究中获得的知识将使我们能够产生具有“隐身”特征的新病毒载体，同时，将突出通常导致强大的炎症和对野生型AD的免疫力的机制。隐形载体将允许更安全的基因转移和更长的转移基因表达。拟议的研究基于我们的初步数据引起的新假设：两种主要类型的抗原呈递细胞（APC） - 阴细胞（DC）和巨噬细胞（MO）调节宿主免疫反应对AD的性质和大小； APC通过AD潜在抗原和表位的受限子集检测病毒。主要的表位位于衣壳蛋白中，但对于两种类型的APC而言是不同的。 DC的主要表位位于Penton Capsid蛋白中。 MO的主要表位位于纤维衣壳蛋白中。我们已经构建了在Penton和Fiber中突变的一组新的AD矢量，这将使我们能够检验这一假设。这些研究的结果不仅将对基因转移应用具有实际意义，而且还将对免疫系统的最早识别病毒识别的最早阶段的基本方面进行新的启示。