ENHANCEMENT OF THE PILOT PROGRAM

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 试点研究计划的目的是吸引新的研究人员，这些研究人员有望在非人类灵长类生物医学研究领域取得良好的职业生涯，或者希望在现有的研究计划中添加非人类灵长类动物的组成部分。 该计划还向已建立非人类灵长类动物研究计划、希望开发实质性新研究方向的研究人员开放。该研究必须有可能向外部资助机构申请强有力的研究资助。 试点研究基金不会为已建立的项目或任何有资格获得其他来源支持的项目提供临时支持。 四个试点项目正在进行中。 SIV 感染的 CD8 耗尽的恒河猴中的周围神经病变：已获得四只动物，接种了 SIVmac251 并耗尽了 CD8 T 细胞。研究的生命阶段已经完成。 目前正在分析血液和组织样本。 SIVmac239 减毒变体发病机制和神经发病机制的遗传决定因素：2010 年 7 月 5 日，四只恒河猴感染了突变的 SIVmac239 SIVmac239¿GY S/P)。根据研究设计，在接种后 28 天对两只动物实施安乐死。我们继续监测剩下的两只动物是否有 SIV 疾病进展的迹象。 迄今为止获得的数据表明，SIVmac239¿GY S/P 是一种比 SIVmac239 ¡GY 更具致病性的病毒，并且 SIVmac239 ¡GY S/P 中发生的突变本质上是补偿性的。 星形胶质细胞是 SIV 相关炎症的关键调节者：本季度，我们注意到，在 mRNA 水平上，星形星形胶质细胞上的关键整合素下调，尤其是整合素 α 6。与此同时，VCAM-1 增加。实验继续在蛋白质水平上证实了这一点。中间丝的表达也发生了改变，包括 GFAP、巢蛋白和波形蛋白。还评估了细胞因子的分泌。我们有一篇论文正在出版，部分由该项目资助：星形胶质细胞产生 MCP-3/CCL7：对 SIV 神经侵袭和艾滋病脑炎的影响 猕猴体内基因沉默：我们现已获得所有相关监管机构（IACUC、IBC 和 TRAC）的许可。四只食蟹猴已被分配到该项目，目前正在隔离中。我们预计将于 2011 年 4 月开始 Mtb 感染。同时，我们正在优化猕猴细胞（骨髓来源的巨噬细胞）中 SOCS3 的沉默，以便确定两对最佳的寡核苷酸，这将使我们有机会进行体内沉默。 最近授予了另外三个试点项目： 中枢神经系统白质束作为克拉伯病基因治疗的新途径 新生猕猴先天免疫的发展 森林登革热病毒在自然灵长类宿主中的复制

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The purpose of the Pilot Research Program is to attract new investigators who show promise of developing a strong career in nonhuman primate biomedical research or who wish to add a nonhuman primate component to their existing research programs. The program is also open to investigators with established research programs using nonhuman primates who wish to develop substantially new research directions. The research must have potential for leading to a strong research grant application to outside funding agencies. Pilot research funds will not provide interim support for established projects or for any projects that qualify for support from other sources. Four pilot projects are ongoing. Peripheral Neuropathy in SIV-infected CD8-depleted rhesus macaques: Four animals have been obtained, inoculated with SIVmac251 and depleted of CD8+ T cells. The in life phase of the study has been completed. Blood and tissue samples are now being analyzed. Genetic Determinants of Pathogenesis and Neuropathogenesis for an Attenuated Variant of SIVmac239: Four rhesus macaques were infected with a mutated SIVmac239 SIVmac239¿GY S/P) on 7/5/10. Two animals were euthanized at 28 days post inoculation as per the study design. We continue to monitor the two remaining animals for signs of SIV disease progression. Data obtained to date indicates that SIVmac239¿GY S/P is a more pathogenic virus than SIVmac239¿GY and that the mutations made in SIVmac239¿GY S/P are compensatory in nature. Astrocytes are Key Regulators of SIV-related inflammation: This quarter, we have noted that, at the mRNA level, key integrins are down regulated on stellated astrocytes, notably integrin alpha 6. Concomitant with this, there is increased VCAM-1. Experiments continue to confirm this at the protein level. There are also altered expression of the intermediate filaments, including GFAP, nestin and vimentin. Cytokine secretion has also been assessed. We have one paper in press, partially funded by this project: MCP-3/CCL7 production by astrocytes: implications for SIV neuroinvasion and AIDS encephalitis In vivo gene silencing in macaques: We have now received clearance from all the regulatory bodies involved (IACUC, IBC and TRAC). Four cynomolgus macaques have been assigned to the project and are currently in quarantine. We expect to begin Mtb infections in April 2011. Meanwhile we are optimizing the silencing of SOCS3 in macaque cells (bone-marrow derived macrophages) in order to settle on two best pairs of oligonucleotides that will give us a chance to perform in-vivo silencing. Three additional pilot projects were recently awarded: CNS white matter tracts as a novel avenue for gene therapy for Krabbe disease Development of innate immunity in neonatal macaques Replication of sylvatic dengue virus in a natural primate host