Investigating Translational De-repression as a Mechanism to Increase Progranulin Levels in iPSC-derived Patient Neurons

额颞性痴呆(FTD)是一种主要的老年前期年龄依赖性痴呆，其临床特征为 特征包括渐进性行为变化和语言障碍。致病基因突变 原颗粒蛋白导致一个功能等位基因的丢失，是FTD的主要原因。这是普遍观察到的 功能原颗粒减少表明单倍体功能不全是潜在的疾病机制。那里 是否迫切需要开发治疗方法来提高因PROGRAIN引起的FTD患者的PRO 缺乏症。这项建议的总体目标是评估对翻译抑制的调节 内源性前颗粒蛋白表达上调原颗粒蛋白水平的机制 内源性的，在生理环境和规则范围内的。如果我们的假设是正确的，通过增加 人类神经元和小胶质细胞中的原颗粒水平，有可能恢复健康的对照表型 以及延缓疾病发病机制和神经退行性变的方面。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。血浆前颗粒蛋白水平降低 大脑也与几种疾病有关的神经退行性变有关，包括 阿尔茨海默病。因此，增加原颗粒蛋白表达的治疗方法的开发可能会 是预防或治疗多种神经退行性疾病的可行策略。

Frontotemporal dementia (FTD) is a major presenile age-dependent dementia characterized by several clinical features including progressive behavioral changes and language impairments. Pathogenic mutations in progranulin lead to loss of one functional allele and are a major cause of FTD. This commonly observed reduction in functional progranulin indicates haploinsufficiency to be the underlying disease mechanism. There is a critical need to develop treatments to increase progranulin in patients with FTD due to progranulin deficiency. The overall objective of this proposal is to evaluate the modulation of a translational repression mechanism of endogenous progranulin expression with the aim to upregulate progranulin protein levels endogenously and within physiological context and regulation. If our hypothesis is correct, by increasing progranulin levels in human neurons and microglia, it may be possible to restore a healthy control phenotype and delay aspects of disease pathogenesis and neurodegeneration. Our studies will also design and test clinically-relevant antisense oligonucleotides to boost progranulin protein levels. Reduced progranulin levels in the brain have also been linked to the neurodegeneration associated with several diseases, including Alzheimer Disease. Therefore, the development of therapies that increase progranulin expression are likely to be a viable strategy for the prevention or treatment of multiple neurodegenerative diseases.