Molecular impact of endolysosomal dysfunction on neuron-glia communication pathways
内溶酶体功能障碍对神经元-胶质细胞通讯途径的分子影响
基本信息
- 批准号:10538113
- 负责人:
- 金额:$ 6.72万
- 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:2023-01-29 至 2025-04-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloid beta-ProteinAmyloid beta-Protein PrecursorAstrocytesBindingBinding ProteinsBrainBrain regionCell physiologyCell surfaceCellsCommunicationComplementComplement component C4ComplexDementiaDisease ProgressionEndosomesEnvironmentEventFunctional disorderGenesGeneticGenetic EngineeringGenetic RiskGenetic TranscriptionGenetic studyGenetically Engineered MouseGliosisGoalsHealthcare SystemsHippocampus (Brain)HumanImpairmentInflammationLeadLearningLinkMediatingMicrogliaMolecularMusMutateMutationNerve DegenerationNeurobiologyNeurodegenerative DisordersNeurogliaNeuroimmuneNeuronsOrganellesPathogenesisPathogenicityPathologyPathway interactionsPatientsProductionProteinsProteomeProteomicsRecyclingResearchRiskRoleSignal PathwaySignal TransductionSynapsesSystemTechnologyTestingTimeamyloid precursor protein processingbrain cellcell typeconditional knockoutcytokinedementia riskexperimental studyglial activationhuman modelhuman pluripotent stem cellin vivoinsightlensmacrophagemolecular pathologynovelpreventprotein aggregationprotein transportreceptorreceptor bindingrisk variantscaffoldsecretion processstem cell modeltau Proteinstooltraffickingtrans-Golgi Network
项目摘要
Project Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia worldwide.
Despite decades of research, there are few therapies that can delay or prevent AD progression. Retrograde
trafficking through retromer-dependent cargo recognition has emerged as a critical cellular process that is
mutated or disrupted in patients with AD and other forms of dementia. Conditional knockout of retromer genes
in neurons leads to increased secretion of Tau and Amyloid β (Aβ), hallmark protein pathologies linked to AD.
This milieu of neuronal-secreted factors leads to inflammation in microglia and astrocytes, two glial cell types
thought to influence the progression of neurodegeneration. In this proposal, I aim to study the cascade of events
linking neuronal retromer disruption to glial inflammation, characterizing the specific cell state changes involved,
and identify the key factors that mediate this effect. I will address this aim using genetically engineered stem cell-
derived models of human neurons, microglia, and astrocytes. Microglia also express retromer components and
upregulate these factors in AD, yet there are few studies of retromer function specifically in microglia. In Aim 2 I
will therefore explore the effects of retromer-related mutations specifically on microglia in the context of early
aging in mice, a comparable time point to when dementia manifests in patients with these mutations. I will
additionally utilize stem cell models to dissect the functional and signaling changes that are induced in microglia
with retromer disruption. Finally, although there have been several studies looking at the effects of retromer on
specific receptors, little is known about the systems-level effects of retromer mutations on protein trafficking to
the endosomes. To identify retromer-dependent signaling pathways that may be pathogenic, I have developed
novel proteomics tools to quantify endosomal proteome changes and will use these tools to compare the effects
of different retromer mutations on neuronal and microglial endosomes. The ultimate goal is to understand how
retromer disruption affects brain cell states and leads to pathogenic signaling changes.
项目摘要
阿尔茨海默病(Alzheimer's disease,AD)是一种神经退行性疾病,是世界范围内最常见的痴呆症。
尽管经过数十年的研究,很少有治疗方法可以延缓或预防AD的进展。逆行
通过依赖于逆转录酶的货物识别的贩运已经成为一个关键的细胞过程,
在AD和其他形式的痴呆患者中突变或破坏。逆转录基因的条件性敲除
在神经元中的这种变化导致Tau和淀粉样蛋白β(Aβ)的分泌增加,这是与AD相关的标志性蛋白质病理学。
这种神经元分泌因子的环境导致小胶质细胞和星形胶质细胞(两种胶质细胞类型)的炎症
被认为会影响神经退化的进程在这个提议中,我的目标是研究
将神经元逆转录酶破坏与神经胶质炎症联系起来,表征所涉及的特定细胞状态变化,
并找出调节这种效应的关键因素。我要用基因工程干细胞来达到这个目的-
人神经元、小胶质细胞和星形胶质细胞的衍生模型。小胶质细胞还表达逆转录酶组分,
在AD中上调这些因子,但很少有专门在小胶质细胞中的retromer功能的研究。In Aim 2 I
因此,将探讨逆转录酶相关突变的影响,特别是在小胶质细胞的背景下,
在小鼠中老化,这一时间点与患有这些突变的患者出现痴呆症的时间点相当。我会
此外,利用干细胞模型来剖析小胶质细胞中诱导的功能和信号变化,
逆转录病毒干扰最后,虽然有几项研究着眼于retromer对
特异性受体,很少有人知道系统水平的影响,逆转录突变对蛋白质运输,
内体为了识别可能致病的逆转录依赖性信号通路,我开发了
新的蛋白质组学工具来量化内体蛋白质组的变化,并将使用这些工具来比较影响
神经元和小胶质细胞内体上不同的逆转录突变。最终目标是了解
逆转录酶破坏影响脑细胞状态并导致致病性信号传导变化。
项目成果
期刊论文数量(0)
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