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：
10025436
负责人：
Mariah S Hahn
金额：
$ 8.1万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025436
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Animal Disease Models Animal Model Autopsy Behavior Behavioral Biochemical Biological Models Biophysics Brain CRISPR/Cas technology Calcium Cell Communication Cells Cellular Assay Complex Confocal Microscopy Congenital neurologic anomalies Custom Development Disease Disease Marker Environmental Risk Factor Extracellular Matrix FRAP1 gene Formulation Functional disorder Genetic Goals Human Hydrogels Image Image Analysis Impairment In Vitro Knowledge Link Maintenance Memory Memory Loss Modeling Modulus Nature Neuraxis Neurodegenerative Disorders Neurons Organoids Outcome Pathway interactions Patients Process Protein Isoforms Protein Translation Pathway Quality of life Reporting Reproducibility Structure Surface Synapses System Tissue Engineering Tissues Translation Initiation Ubiquitin Validation Western Blotting Work base brain tissue causal variant cell type cost design disease phenotype drug discovery effective therapy ethylene glycol in vivo induced pluripotent stem cell mouse model multicatalytic endopeptidase complex mutant neural circuit neural network novel strategies presenilin-1 proteostasis synaptogenesis targeted treatment tau phosphorylation tau-1 three dimensional cell culture three-dimensional modeling tool viscoelasticity

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 ADPSEN1 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.

抽象的。阿尔茨海默氏病（AD）是一种影响美国580万人的神经退行性疾病仅年度费用估计为2900亿美元。该疾病的特征是记忆力丧失和行为异常，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）脑组织的基本变化。而许多类型的中枢神经系统在AD研究中，异常情况有所不同，始终发现突触的失调失调在广告模型系统中进行更改。从机械上讲，已显示突触改变会收敛许多与蛋白质的途径 - 包括mTOR，大噬菌和泛素 - 蛋白酶体系统（UPS）途径 - 提出一种潜在的统一方法来治疗AD。迄今为止，没有有效的治疗针对这些途径的存在，部分原因是我们对这些途径的中心了解广告大脑中的过程。那是有必要加深我们对这些机制的理解开发针对它们的新颖方法。传统上，广告的机械知识已获得体内动物模型和验尸后人大脑的分析。但是，当前的AD动物模型不完全代表人类状况，人类大脑中的分析缺乏供应，吞吐量和实验控制。诱导的多能干细胞（IPSC）已使Live Human访问神经元，但相关研究在很大程度上是在2D塑料表面上进行的。我们提出了3D材料 - 基于基于AD的非调节突触维持和蛋白质的机制的方法在人类中。与替代3D模型（例如类器官）相比，我们的组织工程方法提供了对于高度可重现的生物物理和生化细胞ECM相互作用的自定义设计。我们提出的这些问题的切入点与来自突变蛋白1（PSEN1）的患者得出的IPSC，广告中最典型的家庭突变。我们的3D模型将合并人类ADPSEN1 IPSC衍生的神经元（无神经元）以模拟钥匙细胞 - 细胞相互作用已知在突触中很重要维护。成功完成拟议的目标后，我们将开发出3D人脑的样子组织可以对连接失调突触和网络活动的机制进行更多的深入分析带有蛋白质的途径。这些模型可以用作药物发现和验证中的其他工具与其他体外人类和体内小鼠模型系统相比，管道提供了独特的相关性。