LACTOBACILLI SAFETY STUDIES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该计划将设计和开发一系列有效的和高选择性的基于蛋白质的局部杀微生物剂。该计划的统一主题是使用非致病性粘膜细菌，乳酸杆菌，将这些蛋白质传递到阴道内的粘膜表面。施用表达蛋白质杀微生物剂的乳杆菌的遗传修饰的阴道分离物，预期可防止HIV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，包括管理、微生物学和灵长类动物安全性研究核心。除了在猕猴中进行的产品安全性研究外，还将进行定植条件的优化和乳酸菌与阴道粘膜相关性的组织学评价。 确定生物工程乳酸杆菌的适当给药方案对于确定杀微生物剂的安全性特征至关重要，并将解决乳酸杆菌产生的杀微生物剂对阴道上皮是否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，为先进的研究和开发活动奠定了基础。此外，所有三种方法都针对HIV用于实现其宿主的生产性感染的保守功能机制。因此，这些方法不太可能被病毒蛋白的高度可变性所规避，这是HIV的一个重要特性，它阻碍了有效预防疫苗的开发。

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.