Modeling Basal Forebrain Cholinergic Neurons in Down syndrome

唐氏综合症基底前脑胆碱能神经元建模

• 批准号: 10428549
• 负责人: Jose Luis Martinez
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428549
• 关键词: Address; Affect; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Apoptosis; Attention; Biological; Birth; Cell physiology; Cells; Cognitive; Complex; Data; Degenerative Disorder; Development; Disease; Down Syndrome; Drug Screening; Foundations; Functional disorder; Genetic; Human; Impaired cognition; Impairment; In Vitro; Individual; Intellectual functioning disability; Intellectual impairment; Knowledge; Language; Lead; Learning; Link; Live Birth; Memory; Memory Loss; Modeling; Molecular; Molecular Profiling; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Oxidative Stress; Pathway interactions; Persons; Phenotype; Play; Population; Predisposition; Process; Public Health; Reporter; Research; Risk; Testing; Therapeutic Intervention; Trisomy; Work; age effect; age related; basal forebrain cholinergic neurons; cognitive function; human data; induced pluripotent stem cell; insight; middle age; mitochondrial dysfunction; molecular phenotype; mouse model; neurocognitive disorder; novel; phenotypic biomarker; stem cell model; therapeutic target; translational medicine

ABSTRACT Down syndrome (DS), or trisomy 21, is both a complex neurodevelopmental and neurodegenerative disorder. DS is characterized by altered cortical development resulting in intellectual impairment at birth and Alzheimer’s disease (AD) pathology in middle age. It is estimated that there are more than 400,000 people living with DS in the U.S. Affecting one in every 700 live births, DS the most common genetic form of intellectual disability, which ranges from mild to moderate with deficits in domains including attention and memory. As individuals with DS age, these cognitive functions decline as they develop AD pathology. A critical feature that links cognitive impairment and neurodegeneration in trisomy 21 is the population of neurons that are susceptible in both processes: basal forebrain cholinergic neurons (BFCN). BFCNs play key roles in regulating attention, memory, and learning. Degeneration or impairment of BFCNs lead to memory loss, decreased spatial recognition, and disturbance in language. Degeneration of this population has also been well documented in a diverse range of human neurocognitive disorders, including DS and AD. However, key molecular pathways involved in BFCN degeneration leading to cognitive, memory and learning deficits aren’t well understood. This project will explore the unique differences of BFCNs derived from both isogenic control and DS human derived induced pluripotent stem cells (iPSCs) to better understand the molecular mechanisms that underlie the susceptibility of this subset of neurons and fill a significant gap in the basic understanding of BFCNs. Results will provide foundational data for identifying therapeutic targets for DS, as well as have an impact on our overall understanding of other neurodegenerative diseases such as AD.

抽象的 唐氏综合症（DS）或三体疾病21是复杂的神经发育和神经退行性的 紊乱。 DS的特征是皮质发育改变，导致出生时智力障碍 和中年的阿尔茨海默氏病（AD）病理学。据估计有超过40万 在美国与DS一起生活的人每700个活产，DS是最常见的遗传 智力残疾的形式，范围从轻度到中等，在域中定义包括 注意力和记忆。随着DS年龄的个人，这些认知功能随着它们的发展而下降 广告病理学。连接三三体性的认知障碍和神经退行性关系的关键特征是 在这两个过程中易感的神经元的种群：基本前脑胆碱能神经元 （BFCN）。 BFCN在确定注意力，记忆和学习中起关键作用。变性或 BFCN的损害导致记忆力丧失，空间识别的减少和语言灾难。 该人群的退化也已在人类的潜水员范围内得到充分记录 神经认知障碍，包括DS和AD。但是，涉及BFCN的关键分子途径 导致认知，记忆和学习缺陷的变性尚不清楚。这个项目将 探索源自ISEGENIC CONTROR和DS人类衍生的BFCN的独特差异 诱导多能干细胞（IPSC）更好地了解基于的分子机制 这一子集的神经元的敏感性并填补了BFCN的基本理解的显着空白。 结果将为识别DS的治疗靶点提供基础数据，并具有 对我们对其他神经退行性疾病（例如AD）的总体理解的影响。