Mentoring in Mouse Molecular Pathobiology Research

描述（改编自申请人的摘要）：本申请寻求 支持职业中期调查员指导合适的候选人在鼠标 病理生物学研究 大卫胡索博士是一名独立研究人员， JHU比较医学部的病理学家。 他 越来越多地关注基因工程小鼠的研究， 在他的研究中，了解艾滋病毒的神经发病机制和持久性。 作为 实验动物联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 在过去的十年里， 年 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选择花费 师中之师。 这些研究员和学生提供了一个 招募和指导小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密切联系， 比较医学部。 该司内部日益强调的是 基因工程的表型分析和基因功能研究 小鼠 该大学的计划包括显著扩大设施， 支持突变小鼠的研究。 在JHU有437个使用老鼠的方案 并且每年使用超过7万只老鼠。 这将创建一个 JHU对小鼠病理生物学研究的高度热情。 Huso博士得到了NIH R 01的支持，使用转基因人类细胞因子的小鼠， 建立一个初级神经胶质细胞培养系统来研究艾滋病毒和 小胶质细胞的分化和活化。 细胞储库的清除 在高活性抗逆转录病毒治疗期间携带艾滋病毒的患者， 主要取决于储库靶细胞的特定周转率 人口 大脑中大多数感染HIV-1的细胞是巨噬细胞， 小胶质细胞 中枢神经系统中的分支组织小胶质细胞代表 体内最稳定的细胞之一 病毒可以在这些 静止细胞数年甚至数十年，然后细胞才开始转变。 然而，由于细胞间相互作用的特征不明显， 因子维持脑中的小胶质细胞分支， 由于无法进入，分支小胶质细胞的生物学仍然知之甚少。 拟议的研究可以为艾滋病毒的持久性，小胶质细胞 感染和神经元损伤。 修订后的K26研究计划建议通过使用 HIV共受体，人CCR 5和CD 4：1转基因小鼠），以开发一种 转基因小鼠中HIV神经发病机制和持久性体内模型; 2） 比较HIV-1进入分枝和活化的小胶质细胞; 3） 确定CD 4或CCR 5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.