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

基本信息

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
项目类别：
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&apos 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

项目摘要

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岁以下人群早期发作痴呆的最常见原因。杂合蛋白基因中功能突变的杂合丧失，导致蛋白质的单倍不足大约有30％的家庭FTD病例。促生蛋白是一个分泌的生长因子，具有不同的生物学在调节炎症，大脑发育和溶酶体功能方面的作用，丧失促素蛋白主要与神经变性有关。尽管最近的理解取得了进步易生蛋白相关的FTD疾病机制的相对贡献，不同细胞类型的相对贡献发病机理的特征很差。与血液维持相关的细胞类型功能障碍直到最近才发现脑屏障（例如内皮细胞）在FTD病理生理学中起着核心作用。该提案的总体目的是评估调节调节性前体相互作用的策略目的是使用该相互作用者内源性并在适当的内部上调progranulin蛋白水平 FTD相关细胞类型中的生理环境。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progranulin-的产生和表征缺陷模型是识别疾病相关表型的平台。如果我们的假设正确，请增加与人类FTD疾病相关的细胞中的预粒蛋白水平可能会恢复健康的对照表型，延迟疾病发病机理和神经退行性的方面。我们的研究还将设计和测试临床上相关的反义寡核苷酸以促进前素蛋白水平。由于降低了尿素大脑中的水平与FTD以外的多种神经退行性疾病有关，疗法是增加刚素蛋白的表达也可能具有预防或治疗多种额外的效用神经条件。