Mentoring in Mouse Molecular Pathobiology Research

描述(改编自申请人的摘要)：本申请旨在 支持职业生涯中期的调查员在MICE中指导适当的候选人 病理生物学研究。David Huso博士是一名独立研究员， JHU比较医学部的病理学家。他有 越来越专注于转基因小鼠的研究并使用它们 在他的研究中了解了艾滋病毒的神经发病机制和持久性。作为一名 实验动物综合培训项目的病理学教员 在JHU的医学和比较病理学，Huso博士协助培训 在过去的十年中，这些专业的二十多名兽医研究员 好几年了。此外，至少有两名兽医学生以及 兽医预科学生和兽医助理每年都会选择 该部门的教官职位。这些研究员和学生提供了一批 招募和指导老鼠病理生物学研究的人才。 JHU为小鼠病理生物学研究提供了丰富的环境。目前， JHU支持核心转基因和基因敲除实验室与 比较医学部。该部门内部越来越强调的是 基因工程菌的表型分析和基因功能研究 老鼠。该大学的计划包括显著扩建设施，以 支持突变小鼠的研究。JHU有437个协议使用鼠标 以及不断扩大的每年超过7万只老鼠的使用量。这将创建一个 JHU对小鼠病理生物学研究有很高的热情。 Huso博士得到了NIH R01的支持，使用转基因人类细胞因子的小鼠来 建立原代神经元-神经胶质细胞培养系统以研究HIV和 小胶质细胞的分支和激活。清除蜂窝储水池 在高效抗逆转录病毒治疗期间携带艾滋病毒的是 主要取决于油藏目标单元的特定周转率 人口。大脑中大多数感染HIV-1的细胞是巨噬细胞和 小胶质细胞。中枢神经系统中分支的组织小胶质细胞代表 体内最稳定的细胞类型之一。病毒可能会在这些地方持续存在 在细胞翻转之前，细胞会静止数年甚至数十年。 然而，由于表征不佳的细胞相互作用和未知的可溶物 维持大脑中小胶质细胞分支的因素，因为神经胶质细胞 由于难以接近，分支小胶质细胞的生物学仍鲜为人知。 拟议的研究可能会对艾滋病毒的持久性、小胶质细胞提供新的见解 感染和神经元损伤。 修订后的K26研究计划建议通过以下方式延长这些R01研究 转HIV共受体、人CCR5和CD4：1的小鼠发展成 转基因小鼠体内HIV神经致病和存活模型2) 比较HIV-1在分支和激活的小胶质细胞中的进入情况；以及3)与 测定CD4或CCR5受体结合对超氧化物产生的影响 在小胶质细胞中。

DESCRIPTION (Adapted from the applicant's abstract): This application seeks support for a midcareer investigator to mentor appropriate candidates in mouse pathobiology research. Dr. David Huso is an independent researcher and pathologist in the Division of Comparative Medicine at JHU. He has increasingly focused on studies of genetically engineered mice and uses them in his research to understand HIV neuropathogenesis and persistence. As a pathology faculty member of a combined training program in Laboratory Animal Medicine and Comparative Pathology at JHU, Dr. Huso has assisted in training over two dozen veterinary fellows in these specialities over the past ten years. In addition, at least two veterinary students, as well as preveterinary students and veterinary assistants each year choose to spend preceptorships in the division. These fellows and students provide a pool of talented individuals to recruit and mentor in mouse pathobiology research. JHU provides a rich environment for mouse pathobiology research. Currently, JHU supports core transgenic and knockout laboratories with close ties to the Division of Comparative Medicine. A growing emphasis within the division is on phenotype analysis and gene function studies of genetically engineered mice. Plans for the university include marked expansion of facilities to support studies of mutant mice. There are 437 protocols at JHU which use mice and an ever-expanding annual use of more than 70,000 mice. This creates a high level of enthusiasm for mouse pathobiology research at JHU. Dr. Huso has NIH R01 support to use mice transgenic for human cytokines to create a primary neuronal-glial culture system to study HIV and the ramification and activation of microglia. Clearance of cellular reservoirs that harbor HIV during highly active antiretroviral therapy treatment is mainly dependent on the particular turnover rate of the reservoir target cell population. Most of the HIV-1-infected cells in the brain are macrophages and microglia. Ramified, tissue microglia in the central nervous system represent one of the most stable cell types in the body. Virus could persist in these quiescent cells for years or perhaps even decades before the cells turn over. However, since poorly characterized cellular interactions and unknown soluble factors maintain microglial ramification in the brain and because glial are inaccessible, the biology of ramified microglia is still poorly understood. The proposed studies could give new insights into HIV persistence, microglia infection, and neuronal injury. This revised K26 research plan proposes to extend these R01 studies by using mice transgenic for the HIV co-receptors, human CCR5 and CD4: 1) to develop an in vivo model for HIV neuropathogenesis and persistence in transgenic mice; 2) to compare the entry of HIV-1 in ramified and activated microglia; and 3) to determine the effects of CD4 or CCR5 receptor binding on superoxide production in microglia.