In vivo properties of gene transfer vectors and delivery in cardiovascular system

具体目的：所有这些研究背后的假设是，充分了解基因转移载体的药代动力学和药效学特性，将需要最终开发组织和细胞特异性载体，以实现精确有效的基因传递。因此，这些研究旨在描述基因转移到小鼠和非人灵长类动物以及小鼠和灵长类动物胎儿中的命运和影响，并描述宿主对基因改造的反应。研究的具体目的是：1。研究vsv - g伪型逆转录病毒和慢病毒载体在系统导入小鼠和猕猴以及小鼠和非猕猴胎儿后的分布、药理学特性、转基因表达和细胞效应。2. 表征初始载体与细胞表面受体相互作用的机制，特别关注主要附着分子如糖胺聚糖和选择素的作用。3. 确定宿主对载体及其表达的转基因的免疫反应的性质和程度；4. 测试一种针对动脉粥样硬化病变细胞外LDL特异性抗体在体内表达的影响。5. 表征噬菌体展示肽库向小鼠和猕猴胎儿的传递，并使用体内噬菌体筛选方法鉴定体内胎儿组织中的肽。

SPECIFIC AIMS: The hypothesis underlying all of these studies is that a full understanding of their pharmacokinetic and pharmacodynamic properties of gene transfer vectors will be required for the eventual development of tissue- and cell-specific vector targeting for precise and effective gene delivery. These studies are therefore intended to characterize the fate and effects of gene transfer into mice and a non- human primate and into the mouse and primate fetus and to characterize the host response to the genetic modification. The specific aims of the studies are: 1. to characterize the distribution and pharmacological properties, transgene expression and cellular effects of VSV-G-pseudotyped retrovirus and lentivirus vectors following systematic introduction into mice and macaques and into mouse and non-macaque fetuses. 2. to characterize mechanisms of initial vector interaction with cell surface receptors, with special attention to the role of primary attachment molecules such as glycosaminoglycans and selectins. 3. to determine the nature and extent of the host immune response to the vectors and their expressed transgenes; 4. to test the effects of in vivo expression of an antibody specific for the extra-cellular LDL of atherosclerotic lesions. 5. to characterize delivery of phage display peptide libraries to mouse and macaque fetuses and use in vivo phage panning methods to identify peptides that home to fetal tissues in vivo.