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

额颞性痴呆(FTD)是一种以进行性行为为特征的神经退行性疾病 变化和/或语言障碍。FTD主要影响大脑的额叶和颞叶 被认为是65岁以下人群早发性痴呆症的最常见原因。 原颗粒蛋白基因杂合性功能丧失突变导致蛋白质单倍性不足 约占所有家族性FTD病例的30%。原颗粒蛋白是一种具有独特生物学特性的分泌型生长因子 在调节炎症、脑发育和溶酶体功能等方面发挥作用， 原颗粒主要与神经退行性变有关。尽管最近在理解上取得了进展 在原颗粒相关的FTD疾病机制中，不同类型的细胞对 发病机制尚不明确。与维持血液有关的细胞类型的功能障碍- 直到最近才发现内皮细胞等脑屏障在FTD的病理生理学中起核心作用。 这项提案的总体目标是评估调节调节原颗粒相互作用的策略 目的是利用这种相互作用在内源性和适当的范围内上调前颗粒蛋白水平 FTD相关细胞类型内的生理背景。我们的研究还首次寻求涵盖 诱导性多能干细胞来源的人神经血管原颗粒的制备及鉴定 虚证模型作为识别疾病相关表型的平台。如果我们的假设是正确的，那么 人类FTD疾病相关细胞中的原颗粒水平可能会恢复健康的对照表型， 延缓疾病的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，以提高原颗粒蛋白水平。由于减少了PROGROING 大脑中的水平与FTD以外的多种神经退行性疾病有关，治疗方法 增加原颗粒表达也可用于预防或治疗许多额外的 神经方面的情况。

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.