The neuropathology of cerebellum in spinal muscular atrophy

脊髓性肌萎缩症小脑的神经病理学

• 批准号: 10436518
• 负责人: Jianli Sun
• 金额: $ 40.08万
• 依托单位: DELAWARE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436518
• 关键词: Affect; Anatomy; Autopsy; Behavior; Body Weight decreased; Brain; Brain Stem; Cell Nucleus; Cell physiology; Cells; Cerebellar Cortex; Cerebellar Nuclei; Cerebellum; Cerebral cortex; Data; Defect; Development; Diffusion; Disease; Disease Progression; Electrophysiology (science); FDA approved; Fiber; Functional disorder; Genes; Genetic; Horns; Human; Imaging Techniques; Immunohistochemistry; Individual; Infant Mortality; Knowledge; Lead; Magnetic Resonance Imaging; Measurement; Measures; Membrane; Modeling; Molecular; Morphology; Motor; Motor Cortex; Motor Neurons; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neuraxis; Neuronal Dysfunction; Neurons; Output; Pathology; Patients; Phenotype; Pontine structure; Positioning Attribute; Prognosis; Property; Proteins; Public Health; Publishing; Purkinje Cells; Reporting; Research; Role; Spinal; Spinal Cord; Spinal Diseases; Spinal Muscular Atrophy; Structure; Symptoms; Synapses; System; Techniques; Testing; Thalamic structure; Therapeutic; Ventral Horn of the Spinal Cord; Work; base; gene therapy; imaging study; improved; in vivo; innovation; insight; motor control; motor deficit; motor disorder; motor neuron degeneration; mouse model; network dysfunction; neural circuit; neural network; neuron loss; neuropathology; novel therapeutic intervention; postnatal; preservation; prevent; relating to nervous system; restoration; treatment strategy

This is a resubmission (A1) of application 1R15 NS120154-01, “The neuropathology of cerebellum in spinal muscular atrophy”, which was reviewed in June 2020 at the ZRG1 MDCN-R (86) section. Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. It arises from the mutation of the survival motor neuron one (SMN1) gene. Despite decades of research, its mechanisms of neuropathology are far from clear. The recent US FDA approved SMN restoration therapies (Nusinersen, Zolgensma, and Risdiplam) are effective in rescuing the motor dysfunction but not cure for SMA. It is not clear how long the effect will last, nor whether patients will suffer problems due to dysfunction of SMN deficient neurons in other parts of the nervous system. Accumulating evidence suggests that low levels of SMN not only alter the function of spinal motor neurons, but also of neurons and neural circuits in other parts of the motor network. However, currently there is little understanding of neuronal pathology in SMA beyond the spinal cord motor neuron (MN) circuit. As new treatments allow patients to live longer, knowledge of the role of central motor network in the neuropathology of SMA will be key for developing long-term prognoses and treatment strategies for patients. The objective of this application is to investigate cerebellar pathology and neural circuit dysfunction in SMA mouse models using magnetic resonance imaging (MRI) and electrophysiological techniques. The rational for this project is based on the important role of cerebellum in motor control, the reports of cerebellar pathology in human SMA patients, as well as our preliminary data showing alterations in the structure and function of cerebellar neural network in mouse models of SMA. Our central hypothesis is that in SMA, alterations in the neurons and neural circuits of the cerebellum decrease cerebellar output and alter descending motor commands from the motor cortex and brainstem to the spinal cord, contributing to neuropathology and motor system dysfunction. This central hypothesis will be tested by three specific aims: 1) Identify changes in the morphology and fiber connections of the cerebellum in SMNΔ7 and MN rescue mice by magnetic resonance imaging techniques; 2) Elucidate the functional alteration of cerebellar neurons and neural circuits related to SMA pathophysiology using electrophysiological techniques; 3) Relate changes in cerebellar structure and neural circuit function to SMA disease progression in MN rescue mouse model. To determine the contribution of structural and functional pathology in the cerebellum to the phenotype of SMA, we will use MRI and electrophysiology to investigate the development of neuropathology in the cerebellum at pre-symptomatic (postnatal day 3–4, P3–P4), early- (P7–P8), and end-symptomatic (P12–P13) stage of SMA. The comparison studies between SMNΔ7 and motor neuron MN mouse models will confirm and elucidate the correlation of cerebellar neuropathology with spinal motor neuron dysfunction in SMA mice. Identifying the start and progression of cerebellar neuropathology will indicate how cerebellar structural or functional pathology or both contribute to the SMA phenotype. The proposed research is innovative because it will be the first thorough study of the dysfunction and its mechanisms of the cerebellar neural network in SMA mice with a unique combination of electrophysiological, MRI and immunohistochemical techniques. This kind of study is required to develop a complete systematic understanding of the pathophysiology of SMA, and almost no studies so far have investigated the critical issue of dysfunction in the brain network and its contribution to motor dysfunction. The proposed research is significant because understanding specific abnormalities cerebellar network can lead to new targets for potential therapeutics aimed at preserving motor function in SMA patients.

这是应用程序1R15 NS120154-01的重新提交（A1），“脊柱小脑的神经病理学 肌肉萎缩”，于2020年6月在ZRG1 MDCN-R（86）部分进行了审查。 脊柱肌肉萎缩（SMA）是婴儿死亡率的主要遗传原因。它是由 生存运动神经元（SMN1）基因。尽管进行了数十年的研究，但其神经病理学机制远非明显。 美国FDA最近批准的SMN修复疗法（Nusinersen，Zolgensma和Risdiplam）有效营救 电动机功能障碍，但不能治愈SMA。尚不清楚效果会持续多长时间，或者患者是否会遭受痛苦 由于神经系统其他部位中SMN缺乏神经元功能障碍引起的问题。积累证据 表明低水平的SMN不仅改变了脊柱运动神经元的功能，还改变了神经元和神经元的功能 在电机网络的其他部分。但是，目前对SMA的神经元病理几乎没有了解 脊髓运动神经元（MN）电路。随着新疗法使患者的寿命更长，知道中央的作用 SMA神经病理学中的运动网络将是制定长期预后和治疗策略的关键 患者。 该应用的目的是研究SMA小鼠的小脑病理学和神经回路功能障碍 使用磁共振成像（MRI）和电生理技术的模型。这个项目的理性是基于 关于小脑在运动控制中的重要作用，小脑病理学在人类SMA患者中的报道以及 我们的初步数据显示了SMA小鼠模型中小脑神经网络的结构和功能的变化。 我们的中心假设是，在SMA中，小脑下降的神经元和神经环节的改变 小脑输出和改变从电机皮层和脑干到脊髓的降低电机命令， 导致神经病理学和运动系统功能障碍。该中心假设将通过三个特定目的进行检验： 1）通过磁性确定小脑和MN拯救小鼠小脑的形态和纤维连接的变化 共振成像技术； 2）阐明小脑神经元和与神经元电路的功能改变 使用电生理技术的SMA病理生理学； 3）关联小脑结构和神经回路的变化 MN救援小鼠模型中SMA疾病进展的功能。确定结构和功能的贡献 小脑的病理学到SMA的表型，我们将使用MRI和电生理学研究 SMA的症状前（第3-4天，P3 – P4），早期（P7 – P8）和SMA的末端 - 症状（P12-P13）阶段的小脑神经病理学的发展。 SMNδ7和运动神经元MN小鼠模型之间的比较研究将确认并阐明 小脑神经病理学与SMA小鼠中脊柱运动神经元功能障碍的相关性。确定起点和 小脑神经病理学的进展将指示小脑结构或功能病理学或两者如何贡献 到SMA表型。拟议的研究具有创新性，因为它将是对功能障碍的首次彻底研究 及其在SMA小鼠中的小脑神经网络的机理，具有电生理学，MRI的独特组合 和免疫组织化学技术。需要进行此类研究才能对 SMA的病理生理学，到目前为止几乎没有研究研究了大脑网络功能障碍的关键问题 及其对运动功能障碍的贡献。拟议的研究很重要，因为了解特定的异常 小脑网络可以导致潜在治疗的新靶标，以保护SMA患者的运动功能。