Core C: Human Biology Validation

项目总结/摘要 神经退行性tau蛋白病是中老年人痴呆和帕金森综合征的最常见原因之一。 到成年晚期对于其中一些，tau蛋白病的诊断准确性相当好（超过75%）， 疾病，如进行性核上性麻痹（PSP），但对其他疾病，如皮质基底神经功能障碍， 退化为这些疾病开发更好的生物标志物将有助于诊断，预后和未来 临床试验研究人员在本CWOW中提出的遗传、细胞建模和免疫测定解决了这些问题。 重要的研究目标。发现调节tau蛋白病风险和严重程度的遗传变异 可以为疾病的发病机制提供重要的见解，并阐明靶向治疗的关键途径。 潜在的治疗方法2011年报道了PSP GWAS的三个基因组位点，包括STX 6， EIF 2AK 3和MOBP，但每个多态性影响疾病风险的机制仍然未知。 在项目1和项目2中发现介导对tau蛋白病的敏感性或抗性的遗传因子， 可能需要开发新的资源来阐明每个基因如何在功能上与tau蛋白相关 疾病中的沉积和毒性。核心C将产生新的研究工具，为中心提供 揭示遗传变异介导的疾病风险的潜在机制的手段，以及 确定可能包括多种遗传修饰剂的共同途径， 治疗目标的途径。在该中心，核心C通过其大量的 病理学证实的tau蛋白病，并为研究项目提供服务。特别是要 提供来自人类tau蛋白病大脑的生物材料，以及协助神经病理学 表征和定量人和小鼠中的tau负荷。我们还将验证 tau病理学和项目研究人员的关键发现之间的联系。最后，我们将建立新的检测方法， 为遗传修饰剂和疾病之间的联系提供了机制性的见解。

PROJECT SUMMARY/ABSTRACT Neurodegenerative tauopathies are among the most common causes of dementia and parkinsonism in middle to late adult life. Diagnostic accuracy for tauopathies is reasonably good (over 75%) for some of these disorders, such as progressive supranuclear palsy (PSP), but poor (<50%) for others, such as corticobasal degeneration. Developing better biomarkers for these disorders would be useful for diagnosis, prognosis and future clinical trials. The genetic, cell modeling and immunoassays proposed by investigators in this CWOW address these important research objectives. The discovery of genetic variants that modulate risk and severity of tauopathy could provide significant insight into disease pathogenesis, as well as illuminate key pathways to target for potential therapeutics. Three genomic loci were reported in 2011 for the GWAS of PSP, including STX6, EIF2AK3, and MOBP, but the mechanisms by which each polymorphism impact disease risk remain unknown. Discovery of genetic factors that mediate sensitivity or resistance to tauopathy in Projects 1 and 2 will potentially necessitate development of novel resources to elucidate how each gene is functionally linked to tau deposition and toxicity in disease. Core C will generate new research tools to provide the Center with the means to uncover the underlying mechanisms for risk of disease mediated by the genetic variants, as well as identifying common pathways that potentially include multiple genetic modifiers and would thus represent ideal pathways to target therapeutically. In this Center, Core C plays an essential role through its large collection of pathologically-confirmed tauopathies and for provision of services to the research projects. In particular, we will provide biologic material from human tauopathy brains, as well as assist with the neuropathologic characterization and quantitation of tau burden in humans and mice. We will also validate the relationship between tau pathology and key discoveries by project investigators. Finally, we will establish novel assays to provide mechanistic insight into the link between genetic modifiers and disease.