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：
10353296
负责人：
CATHERINE COOK KACZOROWSKI
金额：
$ 25.97万
依托单位：
JACKSON LABORATORY
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 2023-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353296
关键词：
3-Dimensional 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 Environmental Risk Factor Future Genes Genetic Genetic Models Genetic Risk Genetic Transcription Goals Health Heterogeneity Hippocampus (Brain)Human Huntington Disease Immunohistochemistry Impaired cognition In Vitro Individual Intervention Late Onset Alzheimer Disease Lead Lewy Bodies Link Measures Memory 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 Study models Symptoms System Testing Therapeutic Tissues Vertebral column base brain tissue clinical candidate cognitive enhancement cognitive function cytokine design drug discovery gene network health economics high risk human model humanized mouse mouse model multi-electrode arrays neural network neuropathology new therapeutic target normal aging novel novel therapeutics pre-clinical preclinical study 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.

项目摘要/摘要为了预防目的，发现阿尔茨海默氏病（AD）原因的另一种方法诊断和治疗是研究那些保持认知健康目的地重要遗传的人风险或病理负担，这种现象称为认知弹性。我们寻求了解的本质对正常衰老和AD的认知能力在第一个遗传多样的AD小鼠种群中（AD-BXD）这对人类晚期广告的遗传，转录组和表型异质性进行了建模。基于弹性治疗的靶标。快速识别可能促进认知的化合物临床前研究（体内）及以后的韧性，对于一个概括的系统存在至关重要的需求广告大脑的关键特征，包括形态，细胞 - 细胞相互作用和神经网络在菜肴中的功能（体外）。我们建议使用利用神经元，星形胶质细胞和小胶质细胞开发3D共培养系统在AD-BXD中的认知症状的发作和进展中确定了差异蜂窝弹性的AD和验证该系统以未来发现新的基于弹性的疗法。值得注意的是，化合物的翻译相关性将在体内和跨物种中进行严格评估分析我们和其他人使用各种遗传，OMIC和临床数据进行了开发。我们的长期目标是开发个性化的体外3D测定法，以定量和机械地研究衰老如何变化跨广泛的神经病理学的细胞弹性，以开发出新颖的，有针对性的干预措施增强对潜水员种群的广泛神经退行性疾病的认知健康，利用我们与ICAGEN等制药公司的合作伙伴关系。