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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.

摘要。阿尔茨海默病（AD）是一种神经退行性疾病，在美国影响着580万人