A role for extracellular vesicles in neuroinflammation associated to frontotemporal dementia

细胞外囊泡在额颞叶痴呆相关神经炎症中的作用

基本信息

批准号：
10459119
负责人：
Davide Trotti
金额：
$ 42.9万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459119
关键词：
3-Dimensional ALS patients Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Architecture Astrocytes Autophagosome Behavioral Binding Proteins Biogenesis Biological Models Brain Brain Diseases C9ORF72 Cell model Cells Cerebrum Clinical Complex DNA Sequence Alteration Dipeptides Disease Disease Progression Disease model Engineering Event Frontotemporal Dementia Functional disorder Genes Genotype Gliosis Heart Diseases Human Huntington Disease Immune response In Vitro Individual Inflammation Inflammatory Investigational Therapies Language Lead Link Lipids Lobe Lysosomes Membrane Microglia Modeling Molecular Motor Neurons Multiple Sclerosis Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Nuclear Pore Nucleic Acids Nucleotides Oligodendroglia Organelles Organoids Parkinson Disease Pathogenicity Pathologic Pathology Patients Personality Phase Phenotype Prion Diseases Production Proteins RNA Reporting Research Role Signal Transduction Stimulus Symptoms Temporal Lobe Testing Therapeutic Transcript Translations Traumatic Brain Injury Vesicle Viral astrogliosis base cognitive function design efficacy testing extracellular extracellular vesicles frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis gene repression in vivo Model induced pluripotent stem cell motor neuron degeneration neuroinflammation neuron loss novel therapeutic intervention relating to nervous system stem cells three-dimensional modeling trafficking

项目摘要

Focal neurodegeneration in the frontotemporal lobes of the human brain accounts for the clinical manifestations in frontotemporal dementia (FTD), while gliosis account more for the spreading of pathology and the progression of the disease. Indeed, later stages of FTD are characterized by a substantial, widespread and unresolved microgliosis that is conceivably a result of the spread of neuroinflammation. Despite strong evidence showing glial involvement, the mechanisms underpinning the onset and progression of neuroinflammation and the contribution of glia cells in to the neurodegeneration in FTD are poorly understood. The most common FTD-causative genetic mutation is an intronic hexanucleotide -(GGGGCC)n- repeat expansion occurring in the C9orf72 gene. The same intronic expansion is shared by a subset of amyotrophic lateral sclerosis (ALS) patients, who display motor neuron degeneration related symptoms, which may or may not appear along with the FTD clinical manifestations. C9orf72, in complex with its protein binding partners, SMCR8 and WDR41, is known to regulated lysosomes biogenesis, autophagosomes formation and trafficking of vesicles. In the CNS, the omnidirectional exchange of extracellular vesicles (EVs) is tied to modulation of microgliosis, astrogliosis and to oligodendrocytes maturation. In in vivo models, EVs derived from pro- inflammatory activated microglia can spread the inflammatory status. EVs’ contribution to disease progression has been described in Alzheimer’s disease, ALS, Huntington’s disease, multiple sclerosis, Parkinson’s disease, prion disease, and traumatic brain injury. Conversely, EVs derived from stem cells can mitigate microgliosis and revert the neuroinflammation. In this proposal, we hypothesize that C9orf72 haploinsufficiency, a phenotype reported in C9orf72-linked FTD and ALS patients, defines a new role for EVs in disease. Brain EVs in a C9orf72 deficient background have the potential to drive the progression of neuroinflammation. We will test this hypothesis using human cerebral organoid models cultured from deficient or normal C9orf72 genotypes. We will also assess the therapeutic potential of stem cell derived EVs in treating the progression of neuroinflammation in these models.

人脑额颞叶的局灶性神经变性是临床表现的原因在额颞叶痴呆（FTD）中，神经胶质增生更多地导致病理的扩散和进展事实上，FTD 的后期阶段的特点是严重、广泛且尚未解决。尽管有强有力的证据表明，小胶质细胞增生可能是神经炎症扩散的结果。神经胶质细胞参与、神经炎症发生和进展的机制以及神经胶质细胞在 FTD 神经变性中的作用尚不清楚。最常见的 FTD 致病基因突变是内含子六核苷酸 -(GGGGCC)n- 重复序列发生在 C9orf72 基因中的扩展也被肌萎缩性侧索硬化症的子集所共享。侧索硬化症 (ALS) 患者表现出运动神经元变性相关症状，这些症状可能或可能不与 FTD 临床表现一起出现，与其蛋白结合伙伴复合。 SMCR8 和 WDR41 已知可调节溶酶体生物发生、自噬体形成和运输在中枢神经系统中，细胞外囊泡（EV）的全向交换与调节有关。在体内模型中，EVs 来源于亲-小胶质细胞增生、星形胶质细胞增生和少突胶质细胞成熟。炎症激活的小胶质细胞可以传播炎症状态，从而促进疾病进展。已在阿尔茨海默病、ALS、亨廷顿病、多发性硬化症、帕金森病、朊病毒病和创伤性脑损伤，源自干细胞的 EV 可以减轻小胶质细胞增生和恢复神经炎症。在此提案中，我们追求 C9orf72 单倍体不足，这是 C9orf72 相关 FTD 中报告的一种表型和 ALS 患者，定义了 EV 在 C9orf72 缺陷背景下的疾病中的新作用。我们将使用人类大脑来测试这一假设。我们还将评估从缺陷或正常 C9orf72 基因型培养的类器官模型。干细胞衍生的 EV 在治疗这些模型中神经炎症进展方面的潜力。