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3D Brain Tissue System for Modeling Resilience to Alzheimer's Disease and Drug Discovery

3D 脑组织系统用于模拟阿尔茨海默病和药物发现的恢复能力

基本信息

批准号：
10848925
负责人：
CATHERINE COOK KACZOROWSKI
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10848925
关键词：
3-Dimensional Acceleration Acetylcholinesterase Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Astrocytes Biological Assay Biological Models Cell Communication Cells Clinic Clinical Data Clinical Research Clinical Trials Coculture Techniques Cognitive Cognitive deficits Complex Dementia Diagnosis Disease Drug Screening Economics Environmental Risk Factor Future Genes Genetic Genetic Models Genetic Risk Genetic Transcription Goals Health Heterogeneity Hippocampus Human Huntington Disease Immunohistochemistry Impaired cognition In Vitro Individual Intervention Late Onset Alzheimer Disease Lewy Bodies Link Measures Memory Messenger RNA Microglia Modeling Molecular Morphology Mouse Strains Mus Mutation Nature Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Nootropic Agents Outcome Parkinson Disease Pathologic Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Population Population Heterogeneity Pre-Clinical Model Predisposition Prevention Process Public Health Reproducibility Research Risk Factors Seizures Senile Plaques Silk Societies Staging System Structure Symptoms System Testing Therapeutic Tissues Vertebral column brain tissue cellular resilience clinical candidate cognitive enhancement cognitive function cytokine design drug discovery gene network high risk human model humanized mouse in vivo in vivo Model mouse model multi-electrode arrays neural network neuropathology new therapeutic target normal aging novel novel therapeutics pre-clinical preclinical study promote resilience resilience synaptic function therapeutic evaluation therapeutic target three dimensional cell culture tissue culture transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT An alternative approach to discovering the causes of Alzheimer’s disease (AD) for the purposes of prevention, diagnosis, and treatment is to research individuals who remain cognitively healthy despite significant genetic risk or pathological burden, a phenomenon termed cognitive resilience. Our quest to understand the nature of cognitive resilience to normal aging and AD in the first genetically diverse AD mouse population (the AD-BXDs) that models the genetic, transcriptomic, and phenotypic heterogeneity of human late-onset AD yielded novel targets for resilience-based therapeutics. To rapidly identify compounds that will likely promote cognitive resilience in preclinical studies (in vivo) and beyond, there is a critical need for a system that recapitulates the key features of the AD brain including morphology, cell-cell interactions, and neural network functions in a dish (in vitro). We propose to develop a 3D co-culture system with neurons, astrocytes, and microglia that exploits established differences in the onset and progression of cognitive symptoms in the AD-BXDs to investigate cellular resilience to AD and validate this system for future discovery of novel resilience-based therapeutics. Notably, the translational relevance of compounds will be critically evaluated in vivo and by cross-species analyses that we and others developed using a variety of genetic, omics and clinical data. Our long-term goal is to develop personalized in vitro 3D assays to study, quantitatively and mechanistically, how aging changes cellular resiliency across a broad range of neuropathologies to develop novel, targeted interventions to enhance cognitive health across a broad spectrum of neurodegenerative diseases for diverse populations, leveraging our partnerships with pharmaceutical companies such as Icagen.

项目总结/摘要一种发现阿尔茨海默病（AD）病因以预防为目的的替代方法，诊断和治疗的目的是研究那些尽管存在显著的遗传缺陷，但仍保持认知健康的个体。风险或病理负担，这种现象称为认知弹性。我们对理解宇宙的本质的探索第一个遗传多样性AD小鼠群体（AD-BXD）对正常衰老和AD的认知恢复力对人类迟发性AD的遗传、转录组学和表型异质性进行建模，靶点的药物。为了快速识别可能促进认知能力的化合物，在临床前研究（体内）及以后的恢复中，迫切需要一种系统， AD大脑的关键特征，包括形态学、细胞间相互作用和培养皿中的神经网络功能 (in体外）。我们建议开发一个神经元、星形胶质细胞和小胶质细胞的3D共培养系统，在AD-BXD中认知症状的发作和进展方面建立了差异，以研究细胞对AD的弹性，并验证该系统用于未来发现新的基于毒性的治疗剂。值得注意的是，化合物的翻译相关性将在体内和跨物种进行严格评估。我们和其他人利用各种遗传学、组学和临床数据开发的分析。我们的长期目标是开发个性化的体外3D分析，以定量和机械地研究衰老是如何变化的，细胞弹性在广泛的神经病理学发展新的，有针对性的干预措施，为不同人群增强广泛的神经退行性疾病的认知健康，利用我们与制药公司如Icagen的合作关系。