ENHANCEMENT OF THE PILOT PROGRAM

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 先导研究计划的目的是吸引新的研究人员，他们有希望在非人类灵长类生物医学研究领域发展强大的职业生涯，或者希望在现有的研究计划中增加非人类灵长类成分。该项目也向研究人员开放，这些研究人员利用非人类灵长类动物建立了研究项目，希望开发出实质性的新研究方向。这项研究必须具有向外部资助机构提出强有力的研究资助申请的潜力。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。 目前正在进行四个试点项目。 SIV感染的CD8缺失猕猴的周围神经病变：已获得4只动物，接种SIVmac251并去除CD8T细胞。这项研究的生命阶段已经完成。目前正在对血液和组织样本进行分析。 SIVmac239减毒变异体致病和神经致病的遗传决定因素：4只恒河猴于7/5/10感染SIVmac239 SIVmac239突变株(S/P)，两只动物在接种后28天按研究设计安乐死。我们继续监测剩下的两只动物是否有SIV疾病进展的迹象。到目前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的突变在本质上是补偿的。 星形胶质细胞是SIV相关炎症的关键调节因子：本季度，我们注意到，在mRNA水平上，星形胶质细胞上的关键整合素下调，特别是整合素α6。伴随而来的是VCAM-1的增加。实验继续在蛋白质水平上证实这一点。中间细丝的表达也发生了变化，包括GFAP、Nestin和Vimentin。对细胞因子的分泌也进行了评估。我们有一篇正在出版的论文，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：我们现在已经得到了所有相关监管机构(IACUC、IBC和TRAC)的批准。四只食蟹猴已被分配到该项目，目前正在隔离中。我们预计在2011年4月开始感染结核分枝杆菌。同时，我们正在优化SOCS3在猕猴细胞(骨髓源巨噬细胞)中的沉默，以确定两对最佳的寡核苷酸，使我们有机会在体内进行沉默。 最近又授予了另外三个试点项目： 中枢神经系统白质束作为Krabbe病基因治疗的新途径 新生猕猴先天免疫功能的研究进展 小鼠登革热病毒在灵长类自然宿主中的复制

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