Excitability dysfunction mechanisms underlying the TDP43-dependent ALS and FTD pathogenesis
TDP43 依赖性 ALS 和 FTD 发病机制背后的兴奋性功能障碍机制
基本信息
- 批准号:10651158
- 负责人:
- 金额:$ 63.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:ALS patientsAmygdaloid structureAmyotrophic Lateral SclerosisAnimal ModelAreaAutomobile DrivingBrainCessation of lifeCompensationConflict (Psychology)Corpus striatum structureDNA-Binding ProteinsDataDementiaDiseaseDown-RegulationDrug TargetingElectrophysiology (science)EventExhibitsFDA approvedFrontotemporal DementiaFrontotemporal Lobar DegenerationsFunctional disorderGrantHippocampusHyperactivityImmunohistochemistryIndividualIon ChannelKnowledgeKv2.1 channelLifeLinkMeasuresModelingMotor NeuronsMusMuscle fasciculationMutationNeuronsParalysedPathogenesisPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPlayPublic HealthReportingResearchRiluzoleRoleSeveritiesSpinalSpinal CordSuperoxide DismutaseSymptomsSynapsesTDP-43 aggregationVertebral columnWestern Blottingcholinergiccomorbidityeffective therapyfrontotemporal lobar dementia amyotrophic lateral sclerosismouse modelmutantneuron lossneuronal excitabilityneuroprotectionnew therapeutic targetnovelprotein TDP-43responsesynaptic function
项目摘要
Project Summary/Abstract
Despite much effort to identify mechanisms underlying amyotrophic lateral sclerosis (ALS) and frontotemporal
lobar degeneration dementia (FTLD or FTD), effective treatments remain elusive. Motoneuron (MN) excitability
dysfunction remains the most tightly linked to ALS disease pathology. Much research has reported on disease
alterations in the excitability mechanisms of MNs. However, these data often conflict, as hyperexcitability,
hypoexcitability, and normal excitability have all been seen in animal models of ALS. Such inconsistent data
obscure the role of these excitability changes (i.e., neuroprotective or detrimental). Most of these conflicting
reports are seen in mutant super-oxide dismutase (SOD) models of ALS, the most commonly studied mouse
model of ALS. Our data obtained (via our active grant) from the aggressive G93A SOD mouse model of ALS
suggests that both hypo- and hyperexcitability disease changes might take place concurrently within diseased
MNs. Here, we propose to examine a recent, novel rNLS8 mouse model that recapitulates pathologic
Transactive-response DNA-binding Protein 43 (TDP43) inclusions seen in upper and lower MNs in >90% of ALS
patients, leading to neuronal loss in the brain and spinal cord. TDP43 is specifically seen in most sporadic-onset
ALS cases; thus, between them, the G93A and rNLS8 models represent most ALS, and also FTD, cases.
However, to date, excitability dysregulation has not been examined in this model. Thus, our objective is to
characterize the novel rNLS8 TDP43 mouse model of ALS and compare this data to our existing data from G93A
mice. Both models demonstrate very different disease scenario and progression, yet ultimately both lead to MN
loss and death. By comparing and contrasting mechanisms of excitability dysregulation between these models,
we expect to parse the roles that individual alterations play in ALS/FTD disease pathology via 3 Specific Aims:
Aim 1: Determine MN and synaptic excitability in the rNLS8 model. It is currently unknown whether MN
excitability is altered in the rNLS8 model – as in other ALS models – and whether synaptic excitability dysfunction
is also involved. Thus, we will measure intrinsic MN and synaptic excitability in the rNLS8 model via
electrophysiology recordings, at early, middle, and late disease stages, then contrast them to G93A data.
Aim 2: Determine the roles of ion channels and synaptic inputs in the death of spinal MNs in rNLS8 mice.
We will measure expression levels of ion channels and synapses in spinal MNs of rNLS8 mice at early, middle,
and late disease stages, then contrast them to G93A data.
Aim 3: Determine the roles of ion channels & synaptic inputs in the death of cortical neurons in rNLS8
mice. Loss of cortical neurons in rNLS mice recapitulates key aspects of ALS-comorbid FTD. To examine if
excitability mechanisms involved in the death of spinal MNs are also involved in FTD dementia, we will measure
expression levels of ion channels and synapses in cortical/subcortical neurons of rNLS8 mice at early, mid, and
late disease stages.
项目总结/文摘
项目成果
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Sherif M Elbasiouny其他文献
Sherif M Elbasiouny的其他文献
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{{ truncateString('Sherif M Elbasiouny', 18)}}的其他基金
Mechanisms Underlying Excitability Regulation of Motoneuron Types in ALS
ALS 运动神经元类型兴奋性调节的机制
- 批准号:
9198061 - 财政年份:2015
- 资助金额:
$ 63.39万 - 项目类别:
Mechanisms Underlying Excitability Regulation of Motoneuron Types in ALS
ALS 运动神经元类型兴奋性调节的机制
- 批准号:
10542360 - 财政年份:2015
- 资助金额:
$ 63.39万 - 项目类别:
Mechanisms Underlying Excitability Regulation of Motoneuron Types in ALS
ALS 运动神经元类型兴奋性调节的机制
- 批准号:
10367137 - 财政年份:2015
- 资助金额:
$ 63.39万 - 项目类别: