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:10334501
- 负责人:
- 金额:$ 47.23万
- 依托单位:
- 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:
- 关键词:AddressAutomobile DrivingBrainCessation of lifeClinicalDiseaseDisease MarkerDisease modelEventFDA approvedFunctional disorderGene DeliveryGene ExpressionGenesGeneticGoalsImmunohistochemistryInfant MortalityInjectionsKnowledgeLinkMAP Kinase GeneMediatingMitogen-Activated Protein Kinase InhibitorMonitorMorphologyMotorMotor NeuronsMusN-terminalNerve DegenerationNeurodegenerative DisordersPathogenicityPathologyPathway interactionsPatientsPermeabilityPharmacologyPhenotypePhosphorylationProcessProtein IsoformsPublishingSMN deficiencySMN expressionSMN protein (spinal muscular atrophy)Severity of illnessSpinal Muscular AtrophySynapsesTP53 geneTestingTherapeuticUp-RegulationWorkbasecandidate markercombinatorialdruggable targetinhibitorinsightknock-downmotor neuron degenerationmouse modelneuron lossneuroprotectionnovelpreservationpreventrestorationskeletal muscle wastingspinal pathwaytherapeutic targettranscriptome sequencingtreatment 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)是一种以运动神经元缺失和骨骼肌萎缩为特征的神经退行性疾病。
SMA是由SMN蛋白的普遍缺乏引起的,并且是肌肉萎缩的主要遗传原因。
迄今为止,大多数SMA治疗方法集中于增加SMN表达,
SMN诱导疗法最近已被批准用于SMA。
然而,并非所有患者都对治疗有反应。因此,了解
SMA的潜在机制,并确定SMN-非依赖性治疗方法,可以提高
在这种情况下,运动神经元死亡是一个重要的因素。
因此,预防运动神经元变性具有根本的
SMA治疗的临床意义,并可能延长SMN诱导治疗的机会窗口,
然而,由于对死亡途径的了解有限,
这个项目旨在通过调查来解决这些悬而未决的问题,
SMA中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靶向该途径的ESTA的治疗潜力。
我们所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靶点,
丰富的领域,用于发现不依赖于SMN的疾病修饰药理学方法,
适合SMA的组合治疗。基于我们已发表的和初步的研究,我们将描述
基于我们的假设,即SMN缺陷导致SMA运动神经元死亡的上游机制
触发p38 MAPK/p53-MAPK依赖性神经退行性通路(目的1)。
为SMA开发SMN-非依赖性神经保护方法的目标,我们将确定执行
运动神经元死亡的机制,通过识别和功能表征的下游
SMA中p53依赖性神经退行性变的效应物(目标2)。最后,我们将利用
高选择性,脑渗透性抑制剂,以测试假设,p38 MAPK激活是一个共同的致病性
在不同疾病严重程度的SMA小鼠模型中与运动神经元死亡相关的机制
其抑制是一种可行的治疗方法(目的3)。我们还将评估是否有药理学
抑制p38 MAPK通过在以下范例中保留SMA运动神经元而增强突触重新布线:
联合治疗与SMN上调。成功实现我们的目标有可能
为SMA运动神经元死亡机制提供关键见解,确定新的疾病标志物,
候选目标,以停止神经退行性过程,并建立药理学方法,
因此,本发明提供了用于与SMN诱导疗法组合治疗疾病的神经保护的方法。
项目成果
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{{ truncateString('Livio Pellizzoni', 18)}}的其他基金
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
- 批准号:
10559530 - 财政年份:2020
- 资助金额:
$ 47.23万 - 项目类别:
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
- 批准号:
10087983 - 财政年份:2020
- 资助金额:
$ 47.23万 - 项目类别:
Essential role of Stasimon in motor circuit development and disease
Stasimon 在运动回路发育和疾病中的重要作用
- 批准号:
10312031 - 财政年份:2019
- 资助金额:
$ 47.23万 - 项目类别:
Essential role of Stasimon in motor circuit development and disease
Stasimon 在运动回路发育和疾病中的重要作用
- 批准号:
10531553 - 财政年份:2019
- 资助金额:
$ 47.23万 - 项目类别:
Essential role of Stasimon in motor circuit development and disease
Stasimon 在运动回路发育和疾病中的重要作用
- 批准号:
10057404 - 财政年份:2019
- 资助金额:
$ 47.23万 - 项目类别:
RNA-mediated mechanisms of motor system dysfunction in spinal muscular atrophy
RNA介导的脊髓性肌萎缩症运动系统功能障碍的机制
- 批准号:
10022699 - 财政年份:2019
- 资助金额:
$ 47.23万 - 项目类别:
The Role of p38 MAPK Activation in Spinal Muscular Atrophy
p38 MAPK 激活在脊髓性肌萎缩症中的作用
- 批准号:
9317946 - 财政年份:2017
- 资助金额:
$ 47.23万 - 项目类别:
A genome-wide phenotypic screen for modifiers of SMN expression and function
SMN 表达和功能修饰因子的全基因组表型筛选
- 批准号:
8702410 - 财政年份:2014
- 资助金额:
$ 47.23万 - 项目类别:
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