Upregulation of progranulin in a human iPSC-derived neurovascular model of GRN-associated Frontotemporal Dementia

额颞叶痴呆（Frontotemporal dementia，FTD）是一种以进行性行为学改变为特征的神经退行性疾病， 变化和/或语言障碍。FTD主要影响大脑额叶和颞叶 并且被认为是65岁以下人群中早发性痴呆的最常见原因。 颗粒蛋白前体基因中的杂合性功能丧失突变导致蛋白质的单倍不足 约占所有家族性FTD病例的30%。颗粒蛋白前体是一种分泌性生长因子，具有独特的生物学活性， 在调节炎症、脑发育和溶酶体功能等方面的作用， 颗粒蛋白前体主要与神经变性有关。尽管最近在理解上取得了进展 在前颗粒蛋白相关FTD疾病机制中，不同细胞类型对 发病机制的特征不明显。与维持血液相关的细胞类型功能障碍- 最近才发现脑屏障如内皮细胞在FTD病理生理学中起中心作用。 本提案的总体目标是评估调节颗粒蛋白前体相互作用物的策略 目的是使用该相互作用物内源性地和在适当的范围内上调颗粒蛋白原蛋白水平 FTD相关细胞类型内的生理背景。我们的研究还首次试图涵盖 诱导多能干细胞衍生的人神经血管颗粒蛋白前体的产生和表征- 缺陷模型作为鉴定疾病相关表型的平台。如果我们的假设是正确的， 人FTD疾病相关细胞中的颗粒蛋白前体水平可能恢复健康对照表型， 延缓疾病发病机制和神经退行性变。我们的研究还将设计和测试 临床相关的反义寡核苷酸以提高颗粒蛋白前体蛋白水平。由于还原颗粒蛋白前体 大脑中的水平与FTD以外的多种神经退行性疾病有关， 颗粒蛋白前体表达的增加也可用于预防或治疗许多其它的 神经系统疾病

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by progressive behavioral changes and/or language impairments. FTD predominantly affects the frontal and temporal lobes of the brain and is considered the most common cause of early onset dementia in people under the age of 65. Heterozygous loss of function mutations in the progranulin gene resulting in a haploinsufficiency of the protein contribute to about 30% of all familial FTD cases. Progranulin is a secreted growth factor with distinct biological roles in regulating inflammation, brain development and lysosomal function among others, with loss of progranulin being primarily associated with neurodegeneration. Despite recent advances in the understanding of progranulin-associated FTD disease mechanisms, the relative contribution of different cell types to pathogenesis is poorly characterized. Dysfunction of cell types associated with the maintenance of the blood- brain barrier such as endothelial cells were only recently found to play a central role in FTD pathophysiology. The overall objective of this proposal is to evaluate a strategy to modulate a regulatory progranulin interactor with the aim to use this interactor to upregulate progranulin protein levels endogenously and within appropriate physiological context within FTD relevant cell types. Our studies also seek for the first time to encompass the generation and characterization of an induced pluripotent stem cell-derived human neurovascular progranulin- deficiency model as a platform to identify disease relevant phenotypes. If our hypothesis is correct, increasing progranulin levels in human FTD disease-relevant cells may potentially restore a healthy control phenotype, delaying aspects of disease pathogenesis and neurodegeneration. Our studies will also design and test clinically relevant antisense oligonucleotides to boost progranulin protein levels. Since reduced progranulin levels in the brain have been linked to multiple neurodegenerative diseases beyond FTD, therapies that increase progranulin expression may also have utility for the prevention or treatment of a number of additional neurological conditions.