LACTOBACILLI SAFETY STUDIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该计划将设计和开发一系列有效和高选择性的蛋白质类局部杀微生物剂。该计划的统一主题是使用非致病的粘膜细菌乳杆菌，将这些蛋白质输送到阴道内的粘膜表面。使用表达蛋白质杀微生物剂的转基因乳杆菌阴道分离株有望防止艾滋病毒进入或进入宿主细胞和组织，从而减少感染。产品开发项目由中央核心设施支持，包括行政、微生物学和灵长类安全研究核心。除了在猕猴身上进行产品安全性研究外，还将进行定植条件的优化和乳杆菌与阴道粘膜的组织学评估。确定生物工程乳杆菌的适当剂量方案对于确定杀菌剂的安全性至关重要，并将解决乳杆菌产生的杀菌剂是否对阴道上皮有任何意想不到的影响。 重要的是，本申请中强调的三个独特的产品开发项目已经完成了关键的“概念验证”研究，为高级研究和开发活动奠定了基础。此外，这三种方法都针对HIV使用的保守功能机制，以实现对宿主的有效感染。因此，这些方法不太可能被病毒蛋白的高度变异性所绕过，而病毒蛋白是艾滋病毒的一个重要特性，它损害了有效预防性疫苗的开发。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This program will design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the program is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The product development projects are supported by central core facilities, including administrative, microbiology, and primate safety study cores. In addition to product safety studies conducted in macaques, optimization of colonization conditions and histological evaluation of Lactobacillus association with the vaginal mucosal will be carried out. Determination of an adequate dosing regimen for the bioengineered Lactobacillus will be essential for determining the safety profile of the microbicides, and will address whether there are any unexpected effects of microbicides produced by lactobacilli on vaginal epithelia. Importantly the three unique product development projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for advanced research and development activities. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.