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

研究转化去抑制作为增加 iPSC 衍生患者神经元中颗粒体蛋白前体水平的机制

• 批准号: 9807947
• 负责人: Sandra Almeida
• 金额: $ 46.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807947
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Antisense Oligonucleotides; Atrophic; Behavioral; Brain; C9ORF72; Cells; Clinical; Degenerative Disorder; Dementia; Development; Disease; Family; Frontotemporal Dementia; Functional disorder; Human; Language; Lead; Link; MAPT gene; Microglia; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Open Reading Frames; PGRN gene; Pathogenesis; Pathogenicity; Patients; Personality; Phenotype; Physiological; Prevention strategy; Proteins; Regulation; Repression; Societies; Temporal Lobe; Testing; Therapeutic; Translational Repression; age related; clinically relevant; design; frontal lobe; induced pluripotent stem cell; language impairment; loss of function; loss of function mutation; mutant; therapy development

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.

额颞痴呆（FTD）是一种主要的老年年龄依赖性痴呆，其特征是几个临床 包括渐进行为变化和语言障碍在内的功能。致病突变 促生蛋白会导致一个功能等位基因的丧失，并且是FTD的主要原因。这通常观察到 功能性降低表明单倍不足是潜在的疾病机制。那里 对于由于progranulin引起的FTD患者而开发治疗以增加治疗的迫切需要 不足。该提案的总体目的是评估翻译抑制的调节 内源性植物素表达的机理，目的是上调易生蛋白蛋白水平 内源性和生理环境和调节。如果我们的假设是正确的，则通过增加 人类神经元和小胶质细胞中的尿素水平，可能可以恢复健康的对照表型 以及疾病发病机理和神经变性的延迟方面。我们的研究还将设计和测试 临床上与反义寡核苷酸相关的反义寡核苷酸以促进前植物蛋白水平。降低的前素水平 大脑还与与几种疾病相关的神经变性有关，包括 阿尔茨海默氏病。因此，增加了增加前素蛋白表达的疗法的发展很可能 成为预防或治疗多种神经退行性疾病的可行策略。