Mechanisms and therapeutic targeting of motor neuron death in SMA

SMA 运动神经元死亡的机制和治疗靶向

基本信息

批准号：
10087983
负责人：
Livio Pellizzoni
金额：
$ 47.23万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10087983
关键词：
Address Automobile Driving Brain Cessation of life Clinical Disease Disease Marker Disease model Event FDA approved Functional disorder Gene Delivery Gene Expression Genes Genetic Goals Immunohistochemistry Infant Mortality Injections Knowledge Link MAP Kinase Gene Mediating Mitogen-Activated Protein Kinase Inhibitor Monitor Morphology Motor Motor Neurons Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Pathogenicity Pathology Pathway interactions Patients Permeability Pharmacology Phenotype Phosphorylation Process Protein Isoforms Publishing SMN deficiency SMN expression SMN protein (spinal muscular atrophy)Severity of illness Spinal Muscular Atrophy Synapses TP53 gene Testing Therapeutic Up-Regulation Work base candidate marker combinatorial druggable target inhibitor/antagonist insight knock-down motor neuron degeneration mouse model neuron loss neuroprotection novel preservation prevent restoration skeletal muscle wasting spinal pathway therapeutic target transcriptome sequencing treatment effect

项目摘要

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by ubiquitous deficiency in the SMN protein and is the leading genetic cause of infant mortality. To date, most SMA therapeutic approaches have focused on increasing SMN expression and SMN-inducing therapies have recently been approved for SMA. However, these therapies alone do not provide a cure or SMA nd not all patients respond to treatment. Therefore, it remains essential to understand the underlying mechanisms of SMA and identify SMN-independent therapeutic approaches that can enhance the benefit of SMN-inducing strategies through combinatorial treatment. In this context, motor neuron death is an irreversible pathogenic hallmark of SMA. Therefore, preventing motor neuron degeneration has fundamental clinical implications for SMA therapy and could extend the window of opportunity for SMN-inducing therapies to exert their effect. However, this is hindered by limited knowledge of the death pathway and availability of druggable-targets for halting this process. This project aims to address these outstanding issues by investigating the mechanisms underlying the initiation and execution of motor neuron degeneration in SMA as well as validate the therapeutic potential of pharmacologically targeting this pathway in mouse models of the disease. The premise of our proposed work is that the neurodegenerative pathway of SMA motor neurons represents a target- rich domain for the discovery of disease-modifying pharmacological approaches that are SMN-independent and suited for combinatorial treatment of SMA. Building on our published and preliminary studies, we will characterize the upstream mechanisms driving motor neuron death in SMA based on our hypothesis that SMN deficiency triggers a p38MAPK/p53-dependent neurodegenerative pathway (Aim 1). To broaden the range of candidate targets for developing SMN-independent neuroprotective approaches for SMA, we will determine the execution mechanisms of motor neuron death through the identification and functional characterization of the downstream effectors of p53-dependent neurodegeneration in SMA (Aim 2). Lastly, we will leverage on the availability of a highly selective, brain permeable inhibitor to test the hypothesis that p38MAPK activation is a shared pathogenic mechanism associated with motor neuron death across mouse models of SMA with varying disease severity whose inhibition is a viable therapeutic approach (Aim 3). We will also evaluate whether pharmacological inhibition of p38MAPK enables enhanced synaptic rewiring by preserving SMA motor neurons in a paradigm of combinatorial treatment with SMN upregulation. Successful accomplishment of our objectives has the potential to provide key insights into the mechanisms of motor neuron death in SMA, identify new disease markers and candidate targets to halt the neurodegenerative process, and establish pharmacological approaches for neuroprotection to be used in combinatorial treatment of the disease with SMN-inducing therapies.

脊髓性肌萎缩症（SMA）是一种神经退行性疾病，其特征是运动神经元丧失和骨骼肌萎缩。 SMA 是由 SMN 蛋白普遍缺乏引起的，是导致肌肉萎缩的主要原因。迄今为止，大多数 SMA 治疗方法都集中在增加 SMN 表达和 SMN 诱导疗法最近已被批准用于治疗 SMA。但是，这些疗法本身并不能提供治疗作用。治愈或 SMA 并不是所有患者都对治疗有反应，因此，了解这一点仍然很重要。 SMA 的潜在机制，并确定可增强 SMA 独立性的治疗方法在这种情况下，运动神经元死亡是一种通过组合治疗诱导 SMN 策略的益处。 SMA 的不可逆致病特征因此，预防运动神经元变性具有根本意义。 SMA 治疗的临床意义，并可能延长 SMN 诱导疗法的机会窗口然而，这受到对死亡途径和可用性的有限了解的阻碍。药物靶点来阻止这一过程。该项目旨在通过调查来解决这些悬而未决的问题。 SMA 运动神经元变性的启动和执行机制以及验证在该疾病的小鼠模型中以药理学靶向该途径的治疗潜力。我们提出的工作的前提是 SMA 运动神经元的神经退行性通路代表了一个目标 - 丰富的领域，用于发现不依赖于 SMN 的缓解疾病的药理学方法适合 SMA 的组合治疗根据我们已发表的初步研究，我们将描述其特征。基于我们的假设 SMN 缺陷，驱动 SMA 运动神经元死亡的上游机制触发 p38MAPK/p53 依赖性神经退行性通路（目标 1）。开发独立于 SMN 的 SMA 神经保护方法的目标，我们将确定执行通过下游的识别和功能表征来了解运动神经元死亡的机制 SMA 中 p53 依赖性神经变性的效应器（目标 2）。高选择性、脑渗透性抑制剂，用于测试 p38MAPK 激活是一种共同致病性的假设不同疾病严重程度的 SMA 小鼠模型中运动神经元死亡的相关机制其抑制是一种可行的治疗方法（目标 3）。抑制 p38MAPK 通过在以下范式中保留 SMA 运动神经元来增强突触重新布线与 SMN 上调的组合治疗。我们的目标有成功实现的潜力。提供有关 SMA 运动神经元死亡机制的重要见解，识别新的疾病标记物并候选目标是阻止神经退行性过程，并建立药理学方法神经保护作用与 SMN 诱导疗法联合治疗该疾病。