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

项目摘要/摘要 另一种发现阿尔茨海默病(AD)病因以预防为目的的方法， 诊断和治疗是研究尽管存在显著基因突变但仍保持认知健康的个体 风险或病理性负担，这种现象称为认知复原力。我们想要了解地球的本质 第一个遗传多样性AD小鼠群体(AD-BXD)对正常衰老和AD的认知弹性 对人类迟发性阿尔茨海默病的遗传、转录和表型异质性进行建模的研究产生了新的 基于复原力的疗法的目标。快速识别可能促进认知的化合物 在临床前研究(体内)和以后的研究中，迫切需要一个系统来概括 培养皿中AD大脑的主要特征，包括形态、细胞间相互作用和神经网络功能 (体外)。我们建议开发一种与神经元、星形胶质细胞和小胶质细胞共培养的3D系统，利用 建立AD-BXDS患者认知症状的发病和进展差异调查 细胞对阿尔茨海默病的复原力，并验证这一系统，为未来发现基于复原力的新疗法。 值得注意的是，化合物的翻译相关性将通过体内和跨物种进行批判性评估。 我们和其他人利用各种基因、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 细胞在广泛的神经病理中的弹性，以开发新的、有针对性的干预措施 增强不同人群对各种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。

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.