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

额颞叶痴呆（FTD）是一种主要的老年前期年龄依赖性痴呆，其特征在于多种临床表现 包括渐进性行为变化和语言障碍。致病性突变 颗粒蛋白前体导致一个功能性等位基因丧失，是FTD的主要原因。这通常被观察到， 功能性颗粒蛋白原的减少表明单倍不足是潜在的疾病机制。那里 迫切需要开发治疗方法，以增加因颗粒蛋白前体导致FTD患者的颗粒蛋白前体 缺陷这个建议的总体目标是评估翻译抑制的调制 内源性颗粒蛋白前体表达的机制，目的是上调颗粒蛋白前体蛋白水平 内源性和生理环境和调节内。如果我们的假设是正确的， 如果我们能够降低人类神经元和小胶质细胞中的颗粒蛋白前体水平， 并延缓疾病发病机制和神经变性的各个方面。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颗粒蛋白前体蛋白水平。降低颗粒蛋白前体水平， 大脑也与几种疾病相关的神经变性有关，包括 老年痴呆症因此，增加颗粒蛋白前体表达的疗法的发展可能会 成为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.