A comparative inter-neuronal and inter-species platform to understand neuronal differential sensitivity to neurodegeneration

一个比较神经元间和物种间平台，以了解神经元对神经变性的差异敏感性

基本信息

批准号：
10155389
负责人：
Esteban Orlando Mazzoni
金额：
$ 19.81万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155389
关键词：
ALS pathology ALS patients Affect Amyotrophic Lateral Sclerosis Animal Model Animals Benchmarking Biological Models Biology Caenorhabditis elegans Cell model Cells Cephalic Cessation of life Chemicals Communities Comparative Study Complement Data Devices Disease Drosophila genus Embryo Eye Movements Failure Genetic Goals Human In Vitro Mitotic Modeling Molecular Motor Neurons Mus Muscle denervation procedure Muscular Atrophy Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Paralysed Patients Performance Pluripotent Stem Cells Population Predictive Value Proteome Resistance Spinal Stress System Testing Therapeutic Therapeutic Intervention Translating base cell type chemical genetics comparative design effective therapy embryonic stem cell human model human pluripotent stem cell human stem cells improved in vitro Model in vivo induced pluripotent stem cell inducible gene expression mouse model multicatalytic endopeptidase complex novel oculomotor overexpression programs proteostasis resistance mechanism stem cell differentiation superoxide dismutase 1 tool transcription factor transcriptomics visual tracking

项目摘要

Neurodegenerative diseases are characterized by the selective death of specific neuronal cell types. Although fundamental to understanding neurodegeneration and designing effective therapies, the molecular nature of differential sensitivity to neurodegeneration remains obscure. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle denervation and loss of motor neurons leading to paralysis. However, not all motor neurons are affected equally. While most spinal motor neurons (SpMNs) degenerate during ALS progression, a subset of rostral cranial motor neurons (CrMNs: oculomotor, trochlear and abducens motor neurons) are typically spared, allowing patients to retain eye movement until late stages of the disease. Thus, ALS patients utilize eye tracking devices to communicate until late disease stages. The ALS resistance seems to be a conserved feature since oculomotor and trochlear motor neurons are also more resistant than SpMNs to neurodegeneration in the ALS mouse model expressing human superoxide dismutase 1 (hSOD1) with G93A mutation. We have established an efficient embryonic stem cell differentiation platform that produces ALS-sensitive and -resistant motor neurons. We have validated the predictive power of this in vitro system with embryonically-derived motor neurons and have identified the ability to maintain a healthy proteome as a possible motor neuron intrinsic mechanism to resist ALS. The goal of this application is to generate a predictive human stem cell differentiation system that will complement model organisms to understand the intrinsic neuronal mechanisms that contribute to motor neuron differential ALS sensitivity to deepen our understanding of ALS pathology and inspire effective therapies.

神经退行性疾病的特征是特定神经元细胞类型的选择性死亡。尽管对于理解神经变性和设计有效疗法至关重要，但神经变性差异敏感性的分子本质仍然不清楚。肌萎缩侧索硬化症 (ALS) 是一种致命的神经退行性疾病，其特征是进行性肌肉去神经支配和运动神经元丧失，导致瘫痪。然而，并非所有运动神经元都受到同样的影响。虽然大多数脊髓运动神经元 (SpMN) 在 ALS 进展过程中退化，但头侧颅运动神经元（CrMN：动眼运动神经元、滑车运动神经元和外展运动神经元）的子集通常不会受到影响，从而使患者能够保留眼球运动直至疾病晚期。因此，ALS 患者利用眼动追踪设备进行交流，直至疾病晚期。 ALS 抵抗似乎是一个保守的特征，因为在表达具有 G93A 突变的人超氧化物歧化酶 1 (hSOD1) 的 ALS 小鼠模型中，动眼神经和滑车运动神经元也比 SpMN 对神经变性具有更强的抵抗力。我们建立了高效的胚胎干细胞分化平台，可产生 ALS 敏感和抵抗的运动神经元。我们已经用胚胎衍生的运动神经元验证了该体外系统的预测能力，并确定了维持健康的能力蛋白质组作为运动神经元抵抗 ALS 的可能内在机制。该应用的目标是生成一个预测性人类干细胞分化系统，该系统将补充模型生物体，以了解有助于运动神经元差异 ALS 敏感性的内在神经元机制，从而加深我们对 ALS 病理学的理解并激发有效的治疗方法。