TOWARD 3D HUMAN BRAIN-LIKE TISSUES FOR TARGETING DYSREGULATED SYNAPSE AND PROTEOSTASIS MECHANISMS IN ALZHEIMER'S DISEASE
针对阿尔茨海默病中突触失调和蛋白质稳态机制的 3D 类人脑组织
基本信息
- 批准号:10263966
- 负责人:
- 金额:$ 8.1万
- 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:2020-09-30 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAmyloid beta-ProteinAnimal Disease ModelsAnimal ModelAutopsyBehaviorBehavioralBiochemicalBiological ModelsBiophysicsBrainCRISPR/Cas technologyCalciumCell CommunicationCellsCellular AssayComplexConfocal MicroscopyCongenital neurologic anomaliesCustomDevelopmentDiseaseDisease MarkerEnvironmental Risk FactorExtracellular MatrixFRAP1 geneFormulationFunctional disorderGeneticGoalsHumanHydrogelsImageImage AnalysisImpairmentIn VitroInduced pluripotent stem cell derived neuronsKnowledgeLinkMaintenanceMemoryMemory LossModelingModulusNatureNeuraxisNeurodegenerative DisordersNeuronsOrganoidsOutcomePathway interactionsPatientsProcessProtein IsoformsProtein Translation PathwayQuality of lifeReportingReproducibilityStructureSurfaceSynapsesSystemTissue EngineeringTissuesTranslation InitiationUbiquitinValidationWestern BlottingWorkbasebrain tissuecausal variantcell typecostdesigndisease phenotypedrug discoveryeffective therapyethylene glycolin vivoinduced pluripotent stem cellmouse modelmulticatalytic endopeptidase complexmutantneural circuitneural networknovel strategiespresenilin-1proteostasissynaptogenesistargeted treatmenttau phosphorylationtau-1three dimensional cell culturethree-dimensional modelingtoolviscoelasticity
项目摘要
ABSTRACT. Alzheimer’s disease (AD) is a neurodegenerative disorder affecting 5.8 million people in the US
alone with an estimated $290 billion in annual costs. The disease is characterized by significant memory loss
and behavioral abnormalities that are often devastating to quality of life. Memory and behavior are directly related
to the underlying changes of the central nervous system (CNS) brain tissue. While many types of CNS
abnormalities are differentially reported in AD studies, dysregulated synapse maintenance is consistently found
to be altered across AD model systems. Mechanistically, synapse alterations have been shown to converge on
many pathways related to proteostasis – including mTOR, macroautophagy, and ubiquitin-proteasome system
(UPS) pathways – suggesting a potential unifying approach for treating AD. To date, no effective therapy
targeting these pathways exists, owing in part to our nascent understanding of the interplay between these
processes in the AD brain. Thus, there is a need to deepen our understanding of these mechanisms as well as
to develop novel approaches to target them. Traditionally, mechanistic knowledge of AD has been gained with
in vivo animal models and with analyses of post-mortem human brains. However, current animal models of AD
are not fully representative of the human condition, and analyses in human brains suffer from a lack of supply,
throughput, and experimental control. Induced pluripotent stem cells (iPSCs) have enabled access to live human
neurons, but associated studies have largely been performed on 2D plastic surfaces. We propose a 3D material-
based approach to enable the study of dysregulated synapse maintenance and proteostasis mechanisms of AD
in humans. Compared to alternative 3D models, such as organoids, our tissue engineering approach provides
for a highly reproducible, custom design of biophysical and biochemical cell-ECM interactions. Our proposed
entry point into these questions is with iPSCs derived from patients with mutant presenilin-1 (PSEN1), one of
the most well characterized familial mutations causative of AD. Our 3D models will incorporate human ADPSEN1
iPSC-derived neurons (iNeurons) to mimic key cell-cell interactions known to be important in synapse
maintenance. Upon successful completion of the proposed aims, we will have developed 3D human brain-like
tissues allowing for more in depth analysis of mechanisms linking dysregulated synapses and network activity
with proteostasis pathways. These models can be utilized as additional tools in the drug discovery and validation
pipeline, offering unique relevance compared to other in vitro human and in vivo mouse model systems.
摘要。阿尔茨海默病(AD)是一种神经退行性疾病,在美国影响580万人
仅这一项,每年的成本估计就达2900亿美元。这种病的特点是记忆力明显丧失
和行为异常,这些通常会破坏生活质量。记忆和行为直接相关
中枢神经系统(CNS)脑组织的潜在变化。虽然许多类型的CNS
在AD研究中,异常的报道是不同的,
在AD模型系统中进行更改。从机制上讲,突触的改变已经被证明是集中在
许多与蛋白质稳态相关的途径-包括mTOR、宏自噬和遍在蛋白-蛋白酶体系统
(UPS)途径-这表明了治疗AD的潜在统一方法。迄今为止,没有有效的治疗方法
针对这些途径的存在,部分原因是我们对这些途径之间的相互作用的初步理解,
AD大脑中的过程。因此,有必要加深我们对这些机制的理解,
开发新的方法来瞄准他们。传统上,AD的机械知识已经获得,
体内动物模型和死后人脑的分析。然而,目前的AD动物模型
并不能完全代表人类的状况,人类大脑中的分析缺乏供应,
吞吐量和实验控制。诱导多能干细胞(iPSC)使人类能够获得活体
神经元,但相关的研究主要是在2D塑料表面上进行的。我们提出了一种3D材料-
的方法,使研究失调的突触维持和蛋白质稳态机制的AD
在人类身上。与替代的3D模型(如类器官)相比,我们的组织工程方法提供了
用于生物物理和生物化学细胞-ECM相互作用的高度可重复的定制设计。我们提出的
这些问题的切入点是从患有突变型早老素-1(PSEN 1)的患者中获得的iPSC,
导致AD的最充分表征的家族性突变。我们的3D模型将包含人类AD PSEN 1
iPSC衍生的神经元(iNeurons)模拟已知在突触中重要的关键细胞-细胞相互作用
上维护在成功完成拟议目标后,我们将开发出类似人脑的3D
组织允许更深入地分析连接失调的突触和网络活动的机制
蛋白质代谢途径。这些模型可以作为药物发现和验证的额外工具
管道,提供独特的相关性相比,其他体外人类和体内小鼠模型系统。
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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Mariah S Hahn其他文献
Mariah S Hahn的其他文献
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{{ truncateString('Mariah S Hahn', 18)}}的其他基金
TOWARD 3D HUMAN BRAIN-LIKE TISSUES FOR TARGETING DYSREGULATED SYNAPSE AND PROTEOSTASIS MECHANISMS IN ALZHEIMER'S DISEASE
针对阿尔茨海默病中突触失调和蛋白质稳态机制的 3D 类人脑组织
- 批准号:
10025436 - 财政年份:2020
- 资助金额:
$ 8.1万 - 项目类别:
TOWARDS ELECTRICALLY ENRICHED MESENCHYMAL STEM CELLS FOR TREATMENT OF EARLY INFLAMMATORY OSTEOARTHRITIS
利用电富集间充质干细胞治疗早期炎症性骨关节炎
- 批准号:
9809453 - 财政年份:2019
- 资助金额:
$ 8.1万 - 项目类别:
Macrophage And Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration
巨噬细胞和成纤维细胞对慢性声带疤痕修复的调节
- 批准号:
8713011 - 财政年份:2014
- 资助金额:
$ 8.1万 - 项目类别:
Macrophage And Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration
巨噬细胞和成纤维细胞对慢性声带疤痕修复的调节
- 批准号:
8841337 - 财政年份:2014
- 资助金额:
$ 8.1万 - 项目类别:
Macrophage And Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration
巨噬细胞和成纤维细胞对慢性声带疤痕修复的调节
- 批准号:
9059691 - 财政年份:2014
- 资助金额:
$ 8.1万 - 项目类别:
Macrophage and Fibroblast Modulation Toward Chronic Vocal Fold Scar Restoration
巨噬细胞和成纤维细胞对慢性声带疤痕修复的调节
- 批准号:
9238202 - 财政年份:2014
- 资助金额:
$ 8.1万 - 项目类别:
Generating Vascular Graft Luminal and Medial Layers Based on Multipotent Stem Cel
基于多能干细胞生成血管移植管腔和内侧层
- 批准号:
8441862 - 财政年份:2013
- 资助金额:
$ 8.1万 - 项目类别:
Generating Vascular Graft Luminal and Medial Layers Based on Multipotent Stem Cel
基于多能干细胞生成血管移植管腔和内侧层
- 批准号:
8692757 - 财政年份:2013
- 资助金额:
$ 8.1万 - 项目类别:
Tissue Engineering Evaluation of Material Implants for Vocal Fold Restoration
声带修复材料植入物的组织工程评估
- 批准号:
7850307 - 财政年份:2009
- 资助金额:
$ 8.1万 - 项目类别:
Tissue Engineering Evaluation of Material Implants for Vocal Fold Restoration
声带修复材料植入物的组织工程评估
- 批准号:
7387803 - 财政年份:2007
- 资助金额:
$ 8.1万 - 项目类别:
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