Core--Neurohistology, Genomic and Bioinformatic Analyses

这一核心为NIH PD Udall中心联盟和其他PD科学家提供了独特的数据和方法，用于(1)临床上的PD细胞治疗原型，以及项目6-7中开发的潜在未来临床试验参数。(2)用于人类干细胞来源和胎儿DA神经元的新的人多巴胺(DA)细胞标志物，以及(3)在项目5的PD啮齿动物功能和神经保护模型中评估人类基因的原位和免疫细胞化学。重要的是，由Core执行的组织学和共聚焦体视学提供了有价值的人类移植数据：包括大小、位置、特定DA神经元的数量、表现A9或A10表型的相对比例、它们的分布、重新支配人类宿主大脑的能力。项目6-7对移植到灵长类动物体内的人类干细胞来源的多巴胺神经元进行了类似的研究。因此，核心的工作提供了 独特的数据、功能和专业知识，为帕金森病患者神经元移植的潜在改进提供了洞察力。该核心整合了来自5个外部PD临床小组的人体移植数据。这些团队使用了不同的细胞制剂和手术技术，并提供了接受含有人胎儿DA细胞移植的PD患者的临床数据和死后组织。我们有9例帕金森病死后移植病例，预计每年还会增加4-6例。生物统计和统计神经成像实验室(McLean医院Nick Lange博士)分析临床数据的纵向关系，并将这些数据与尸检组织学数据和活体数据(包括PET)相关联。该核心还为Project 5和与杜克大学NIH Udall PD Center的联合体在人体组织分析中提供了必要的功能，以识别人类SN和VTA中的差异基因表达以及与PD基因座的遗传连锁(Duke协作)。神经退行性变或保护性作用 在杜克大学Udall中心，通过连锁分析(我们目前有27个基因)，与PD相关的差异表达候选基因被Core在PD或年龄匹配的未受影响的中脑组织中进一步探索和定位。该核心将提供(1)在世界各地的临床中心对不同的人类胎儿DA移植物进行PD测试的第一次比较神经学检查，以及(2)人类干细胞的标记和类似分析 DA神经元(项目6-7)。(3)识别帕金森病易损细胞群的相关基因和性状的标记和原位分析。

This core provides unique data and methodology to the NIH PD Udall Center Consortium and other PD scientists for (1) PD cell therapy prototypes in the clinic, and for potential future clinical trial parameters developed in Projects 6-7. (2) Novel human dopamine (DA) midbrain cell markers used for human stem cell derived and fetal DA neuronal characterization, and (3) In-situ and immunocytochemistry of human genes evaluated in PD rodent functional and neuroprotection models of Project 5. Critically, histology and confocal stereology performed by the Core, provides valuable human transplant data: including size, location, number of specific DA neurons, relative proportions exhibiting an A9 or A10 phenotype, their distribution, capacity to reinnervate the human host brain. Analogous studies are made of the human stem cell derived dopamine neurons transplanted in primates of Projects 6-7. The Core's work thus provides unique data, functions and expertise, which generate insights for a potential refinement of neuronal transplantation for PD patients. The Core integrates the human transplantation data from 5 external PD clinical groups. These teams have used different cell preparations and surgical techniques and supplies clinical data and postmortem tissue from PD patients whom received human fetal DA cell containing grafts. We have 9 PD post-mortem transplant cases and expect 4-6 additional cases per year. The Biostatistics and Statistical Neuroimaging Lab (Dr Nick Lange, McLean Hospital) analyzes longitudinal relationships of the clinical data and correlate those with postmortem histological data and in vivo data, including PET. The Core also provides a necessary function for Project 5 and the consortium with Duke U. NIH Udall PD Center in the analyses of human tissue for identifying differential gene expression in human SN and VTA and genetic linkage to PD loci (Duke collaboration). The neurodegenerative or protective roles of differentially expressed candidate genes associated with PD by linkage analysis (we currently have 27 genes) at Duke University Udall Center, are further explored and mapped by the Core in PD or age-matched unaffected midbrain human tissue. The core will provide (1) The first comparative neurological examination of different human fetal DA grafts tested in PD for clinical centers worldwide and (2) Markers and analogous analyses of human stem cell derived DA neurons (for Project 6-7). (3) Markers and in-situ analyses of human dopamine neurons related to genes and traits that identify vulnerable ceil populations in PD.