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

GRN 相关额颞叶痴呆的人 iPSC 衍生神经血管模型中颗粒体蛋白前体的上调

• 批准号: 10789724
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10789724
• 关键词: Ablation; Affect; Age; Alleles; Alzheimer' s Disease; Antisense Oligonucleotides; Atrophic; Behavioral; Biological; Blood - brain barrier anatomy; Brain; C9ORF72; Cells; Clinical; Degenerative Disorder; Dementia; Development; Disease; Down-Regulation; Endothelial Cells; Family; Frontotemporal Dementia; Functional disorder; Generations; Growth Factor; Human; Inflammation; Language; Link; Loss of Heterozygosity; MAPT gene; Maintenance; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; PGRN gene; Pathogenesis; Patients; Personality; Persons; Phenotype; Physiological; Play; Population; Prevention; Proteins; Risk; Role; Senility; Societies; Temporal Lobe; Testing; Therapeutic; Time; Up-Regulation; Work; brain cell; brain endothelial cell; brain tissue; cell type; clinically relevant; design; disease phenotype; early onset; endothelial dysfunction; frontal lobe; induced pluripotent stem cell; language impairment; loss of function; loss of function mutation; mutant; nervous system disorder; neurovascular; novel

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.

额颞叶痴呆（FTD）是一种神经退行性疾病，其特征是进行性行为 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的最常见原因。 颗粒体蛋白前体基因杂合性功能缺失突变导致蛋白质单倍体不足 约占所有家族性 FTD 病例的 30%。颗粒体蛋白前体是一种分泌性生长因子，具有独特的生物学特性 在调节炎症、大脑发育和溶酶体功能等方面的作用， 颗粒体蛋白前体主要与神经变性有关。尽管最近在理解上取得了进展 颗粒体蛋白前体相关 FTD 疾病机制的研究，不同细胞类型对 FTD 疾病的相对贡献 发病机制尚不清楚。与维持血液有关的细胞类型功能障碍 最近才发现内皮细胞等脑屏障在 FTD 病理生理学中发挥着核心作用。 该提案的总体目标是评估调节颗粒体蛋白前体相互作用因子的策略 目的是利用该相互作用因子在适当的范围内内源性上调颗粒体蛋白前体的水平 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 诱导多能干细胞衍生的人神经血管颗粒体蛋白前体的产生和表征 缺陷模型作为识别疾病相关表型的平台。如果我们的假设正确，则增加 人类 FTD 疾病相关细胞中的颗粒体蛋白前体水平可能会恢复健康的对照表型， 延缓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。由于颗粒体蛋白前体减少 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 增加颗粒体蛋白前体表达也可用于预防或治疗许多其他疾病 神经系统疾病。