ENHANCEMENT OF THE PILOT PROGRAM

加强试点计划

• 批准号: 8358185
• 负责人: ANDREW A LACKNER
• 金额: $ 6.84万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358185
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Astrocytes; Attenuated; Award; Biomedical Research; Blood specimen; Bone Marrow Cells; CCL7 gene; CD8B1 gene; Data; Dengue Virus; Development; Disease Progression; Encephalitis; Funding; Funding Agency; Gene Silencing; Genetic Determinism; Glial Fibrillary Acidic Protein; Globoid cell leukodystrophy; Grant; IACUC; Infection; Inflammation; Integrin alpha6; Integrins; Intermediate Filaments; Life; Macaca; Macaca mulatta; Messenger RNA; Monitor; Mutate; Mutation; Mycobacterium tuberculosis; National Center for Research Resources; Natural Immunity; Nature; Neonatal; Neuropathogenesis; Oligonucleotides; Paper; Pathogenesis; Peripheral Nervous System Diseases; Phase; Pilot Projects; Primates; Principal Investigator; Production; Proteins; Qualifying; Quarantine; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Resources; SIV; Source; T-Lymphocyte; Tissue Sample; United States National Institutes of Health; Variant; Vascular Cell Adhesion Molecule-1; Vimentin; Virus; career; cost; cytokine; gene therapy; in vivo; macrophage; nestin protein; nonhuman primate; novel; programs; research study; white matter

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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 试点研究计划的目的是吸引新的研究人员，他们有希望在非人灵长类动物生物医学研究中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灵长类动物成分。 该计划也开放给研究人员，他们已经建立了使用非人灵长类动物的研究计划，希望开发新的研究方向。该研究必须有可能导致一个强大的研究资助申请外部资助机构。 试点研究基金将不为既定项目或任何有资格获得其他来源支助的项目提供临时支助。 四个试点项目正在进行中。 SIV感染的CD 8耗尽的恒河猴中的周围神经病变：已经获得四只动物，用SIVmac 251接种并耗尽CD 8 + T细胞。研究的活体阶段已完成。 血液和组织样本正在分析中。 SIVmac 239减毒变体的发病机制和神经发病机制的遗传决定因素：2010年7月5日，用突变的SIVmac 239（SIVmac 239戈伊S/P）感染四只恒河猴。根据研究设计，在接种后28天对两只动物实施安乐死。我们继续监测其余两只动物的SIV疾病进展迹象。 迄今为止获得的数据表明，SIVmac 239戈伊S/P是比SIVmac 239戈伊致病性更强的病毒，并且SIVmac 239戈伊S/P中产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α 6。与此同时，VCAM-1增加。实验继续在蛋白质水平上证实这一点。中间纤维的表达也发生改变，包括GFAP、巢蛋白和波形蛋白。还评估了细胞因子分泌。我们有一篇论文正在出版中，部分由该项目资助：星形胶质细胞产生MCP-3/CCL 7：SIV神经侵袭和艾滋病脑炎的影响 猕猴体内基因沉默：我们现在已经收到了所有相关监管机构（IACUC，IBC和TRAC）的许可。四只食蟹猴已被分配到该项目，目前处于隔离状态。我们预计在2011年4月开始开始结核分枝杆菌感染。与此同时，我们正在优化猕猴细胞（骨髓来源的巨噬细胞）中SOCS 3的沉默，以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。 最近又批准了三个试点项目： 中枢神经系统白色物质束作为Krabbe病基因治疗的新途径 新生猕猴天然免疫的发育 森林登革热病毒在自然灵长类宿主中的复制