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.

额颞叶痴呆 (FTD) 是一种主要的老年前年龄依赖性痴呆，其特征为多种临床症状 特征包括进行性行为改变和语言障碍。致病性突变 颗粒体蛋白前体会导致一个功能性等位基因的丧失，并且是 FTD 的主要原因。这种常见的观察 功能性颗粒体蛋白前体的减少表明单倍体不足是潜在的疾病机制。那里 由于颗粒体蛋白前体，迫切需要开发增加 FTD 患者颗粒体蛋白前体的治疗方法 不足。该提案的总体目标是评估翻译抑制的调节 内源性颗粒体蛋白前体表达的机制，旨在上调颗粒体蛋白前体蛋白水平 内源性且在生理背景和调节范围内。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颗粒体蛋白前体的水平，有可能恢复健康的对照表型 并延迟疾病发病机制和神经变性的方面。我们的研究还将设计和测试 临床相关的反义寡核苷酸可提高颗粒体蛋白前体蛋白水平。颗粒体蛋白前体水平降低 大脑还与多种疾病相关的神经变性有关，包括 阿尔茨海默病。因此，增加颗粒体蛋白前体表达的疗法的开发可能会 成为预防或治疗多种神经退行性疾病的可行策略。