Microglial regulation of neuronal activity in TDP-43 neurodegeneration
TDP-43 神经变性中神经元活动的小胶质细胞调节
基本信息
- 批准号:10667234
- 负责人:
- 金额:$ 218.82万
- 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:2023-05-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAmyotrophic Lateral SclerosisCellsCentral Nervous SystemCharacteristicsChronicDNA-Binding ProteinsDendritesDependenceDiseaseDisease ProgressionElectron MicroscopyFrontotemporal DementiaGene ExpressionGeneticGenetic InductionHeterogeneityHyperactivityImmuneMicrogliaModelingMusMyeloid CellsNerve DegenerationNeurodegenerative DisordersNeuronsPatientsPhaseProcessProliferatingRecoveryRegulationReportingRodRoleShapesSignal TransductionSynapsesTestingawakefrontotemporal lobar dementia amyotrophic lateral sclerosisgenetic approachglial activationimaging modalityimprovedin vivo two-photon imaginginnovationinsightmouse modelneuronal circuitryneuroprotectionneurotransmissionnovelprotein TDP-43protein aggregationreceptorresponsespatiotemporaltargeted treatmenttherapeutic targettwo-photon
项目摘要
PROJECT SUMMARY
Microglia, as the resident immune cells of the central nervous system, are key players in aging and
neurodegenerative diseases, such as Alzheimer’s disease (AD) and AD-related dementias (ADRD). However,
how microglia sense and regulate neurodegeneration remains largely unknown. TDP-43 is a DNA-binding
protein that is a main component of the protein aggregates found in amyotrophic lateral sclerosis (ALS),
frontotemporal lobar dementia (FTLD), and AD. We used inducible mouse model of TDP-43 translocation
(rNLS8) that can mimic characteristic features of TDP-43 related neurodegeneration. Utilizing in vivo two-
photon imaging, we have demonstrated that rNLS8 mice show neuronal hyperactivity in the cortex during
disease progression, which is associated with unique rod-shaped microglia aligning along neuronal dendrites
in the layer 4 cortex. Based on these exciting observations, we hypothesize that microglia have
neuroprotective roles by regulating cortical microcircuit and attenuating neuronal hyperactivity in
response to TDP-43 related neurodegeneration. We will test this hypothesis with the following three Aims:
Aim 1: Determine the functional heterogeneity of microglial activation in TDP-43 neurodegeneration.
We will use chronic, in vivo two-photon imaging to determine the spatiotemporal activation of microglia,
including process dynamics, landscape changes, and proliferation. In addition, we will examine microglial Ca2+
activity using a newly developed microglial GCaMP7s mouse line and TREM2 dependence. The results from
this aim will uncover microglial heterogeneity in different phases of TDP-43 related neurodegeneration.
Aim 2: Investigate how microglia regulate cortical microcircuits in TDP-43 neurodegeneration. We will
study microglia-neuron interactions in different cortical layers during disease progression and recovery in
rNLS8 mice using simultaneous two-photon and electron microscopy. We will also determine how microglial
TREM2 regulates neuronal circuits, particularly during the early phases of disease progress, in TDP-43 related
neurodegeneration.
Aim 3: Manipulate microglia as a potential therapeutic target in TDP-43 neurodegeneration. We will
precisely control microglial function using chemogenetics in the different phases of disease and delineate
microglial contributions. In addition, we will target TREM2 for treatment of TDP-43 related neurodegeneration.
Our group is perfectly poised to exploit novel methods of imaging microglia-neuron interactions and study their
precise function in aging and TDP-43 related neurodegeneration like ALS, FTLD and AD. These innovative
approaches will provide transformative insights into microglial mechanisms of regulating TDP-43 related
neurodegeneration and spawn putative therapeutic targets that will ultimately help patients with ALS, FTLD,
AD, and ADRD.
项目摘要
小胶质细胞作为中枢神经系统的常驻免疫细胞,是衰老和
神经退行性疾病,如阿尔茨海默病(AD)和AD相关性痴呆(ADRD)。但是,在这方面,
小胶质细胞如何感知和调节神经变性仍然是未知的。TDP-43是一种DNA结合剂,
是肌萎缩侧索硬化症(ALS)中发现的蛋白质聚集体的主要成分的蛋白质,
额颞叶痴呆(FTLD)和AD。我们采用诱导型TDP-43易位小鼠模型,
(rNLS 8),其可以模拟TDP-43相关神经变性的特征性特征。利用体内两个-
光子成像,我们已经证明,rNLS 8小鼠显示在皮层神经元过度活跃,
疾病进展,这与独特的杆状小胶质细胞沿沿着神经元树突排列有关
在第四层皮层。基于这些令人兴奋的观察,我们假设小胶质细胞具有
通过调节皮层微回路和减弱神经元过度活跃来发挥神经保护作用,
对TDP-43相关神经变性的反应。我们将通过以下三个目标来检验这一假设:
目的1:确定TDP-43神经变性中小胶质细胞激活的功能异质性。
我们将使用慢性的体内双光子成像来确定小胶质细胞的时空激活,
包括过程动态、景观变化和扩散。此外,我们将检查小胶质细胞Ca 2 +
使用新开发的小胶质细胞GCaMP 7s小鼠系的活性和TREM 2依赖性。的结果
该目的将揭示TDP-43相关神经变性的不同阶段中的小胶质细胞异质性。
目的2:研究小胶质细胞如何调节TDP-43神经变性中的皮层微电路。我们将
研究疾病进展和恢复期间不同皮质层中的小胶质细胞-神经元相互作用,
rNLS 8小鼠,同时使用双光子和电子显微镜。我们还将确定小胶质细胞
TREM 2调节神经元回路,特别是在疾病进展的早期阶段,与TDP-43相关。
神经变性
目的3:操纵小胶质细胞作为TDP-43神经变性的潜在治疗靶点。我们将
在疾病的不同阶段使用化学遗传学精确控制小胶质细胞功能,
小胶质细胞的贡献。此外,我们将靶向TREM 2用于治疗TDP-43相关的神经变性。
我们的团队完全准备好开发成像小胶质细胞-神经元相互作用的新方法,并研究它们的相互作用。
在衰老和TDP-43相关的神经变性如ALS、FTLD和AD中的精确功能。这些创新
这些方法将为调节TDP-43相关的小胶质细胞机制提供变革性的见解。
神经退行性变和产生推定的治疗靶点,最终将帮助ALS,FTLD,
AD和ADRD。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Long-Jun Wu', 18)}}的其他基金
How microglia sense and regulate neuronal activity in the adult brain
小胶质细胞如何感知和调节成人大脑中的神经元活动
- 批准号:
10671376 - 财政年份:2023
- 资助金额:
$ 218.82万 - 项目类别:
Astrocytic and microglial apoE in aging and AD
星形胶质细胞和小胶质细胞 apoE 在衰老和 AD 中的作用
- 批准号:
10407945 - 财政年份:2021
- 资助金额:
$ 218.82万 - 项目类别:
Astrocytic and microglial apoE in aging and AD
星形胶质细胞和小胶质细胞 apoE 在衰老和 AD 中的作用
- 批准号:
10667470 - 财政年份:2021
- 资助金额:
$ 218.82万 - 项目类别:
Neuroprotective function of microglial TREM2 in TDP43-related neurodegeneration
小胶质细胞TREM2在TDP43相关神经变性中的神经保护功能
- 批准号:
9975271 - 财政年份:2020
- 资助金额:
$ 218.82万 - 项目类别:
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