CNS Stem Cells for neurodegenerative disease research

中枢神经系统干细胞用于神经退行性疾病研究

• 批准号: 8636329
• 负责人: George A. Carlson
• 金额: $ 25.8万
• 依托单位: MC LAUGHLIN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636329
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amino Acid Sequence; Animals; Asses; Brain; Brain Diseases; Cell Death; Cell Line; Cell Survival; Cell Transplants; Cells; Dementia; Discrimination; Disease; Disease model; Economics; Environment; Evaluation; Fiber; Fluorescence; Frontotemporal Dementia; Genes; Genetic; Human; Impaired cognition; Knockout Mice; Life; Methods; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Newborn Infant; Pathology; Pilot Projects; PrPSc Proteins; Predisposition; Prion Diseases; Process; Production; Research; Senile Plaques; Societies; Stem cell transplant; Stem cells; Structure; Synapses; Synaptophysin; System; Tauopathies; Therapeutic Agents; Therapeutic Intervention; Time; Tomatoes; Transgenes; Transplantation; congenic; extracellular; mutant; neurofibrillary tangle formation; neuron loss; novel strategies; prevent; prion-like; protein misfolding; public health relevance; research study; synaptogenesis; tau Proteins; tau aggregation; tau expression; therapy development; tool

Project Summary Neurodegenerative protein misfolding diseases, the most common of which is Alzheimer's disease (AD), exact devastating personal and economic tolls on society. CNS stem cell (CNS-SC) transplantation has been touted, justifiably, as a promising approach for treatment of Alzheimer's disease (AD) and other degenerative brain diseases either by replacing lost cells or as a vehicle for delivery of therapeutic agents. CNS-SC transplantation also may offer new approaches for dissecting disease processes and mechanisms. The broad aim of this pilot project is to assess and refine neurosphere transplantation as a tool to dissect pathogenic mechanisms and spread of tau pathology. Two paradigms will be explored: 1) transplantation of CNS-SC containing neurospheres from mice that do not develop disease into disease models, and 2) transplantation of neurospheres from disease models into mice that do not develop disease. The substrate for these pilot studies is the well-characterized rTg(tauP301L)4510 model for the tauopathy frontotemporal dementia (FTD). AD is characterized by extracellular Ass amyloid plaques and intracellular neurofibrillarly tangles (NFTs) composed of aggregated tau protein. Of the two, NFTs are more tightly associated with cognitive decline, neuron loss, and dementia than are plaques, arguing for the relevance of the FTD model for AD as well as other tauopathies. Evidence suggests that soluble extracellular forms of tau, rather than intracellular neurofibrillary tangles (NFTs), may be the triggers of neuronal dysfunction and cell death. Experiments will compare transplants of neurospheres from eGFP-expressing tau null and mouse tau-expressing mice into newborn rTg(tauP301) and rTg(tauwt) mice that express comparable levels of human mutant or wild type tau, and track cell survival, differentiation into neurons, and synapse formation by the progeny of the transplanted cells. In addition to addressing the question of whether endogenous tau expression is required for deleterious effects of extracellular tau aggregates, replacement of lost host neurons will be assessed. The project will address the questions of whether neurons from rTg(tauP301L) neurospheres develop tauopathy and whether spread of tauopathy is influenced by mismatching of tau primary structures in the transplant and the host. Refined methods and tools will be developed to facilitate application of stem cell transplantation to understanding disease mechanisms; these should prove valuable beyond this specific project.

项目摘要 神经退行性蛋白质错误折叠疾病，其中最常见的是阿尔茨海默病（AD）， 对社会造成毁灭性的个人和经济损失。CNS干细胞（CNS-SC）移植 被吹捧为治疗阿尔茨海默病（AD）和其他疾病的有前途的方法。 通过替换丢失的细胞或作为递送治疗性药物的载体， 剂. CNS-SC移植也可能为解剖疾病过程提供新的方法， 机制等这个试验项目的主要目的是评估和完善神经球移植作为一种治疗方法。 工具来剖析致病机制和tau病理学的传播。将探讨两种范例：1） 移植来自未发病小鼠的含有CNS-SC的神经球 模型，以及2）将来自疾病模型的神经球移植到不发育的小鼠中， 疾病用于这些先导研究的底物是用于该化合物的充分表征的rTg（tauP 301 L）4510模型。 额颞叶痴呆（FTD）。AD的特征在于细胞外A β淀粉样蛋白斑块， 由聚集的tau蛋白组成的细胞内神经原纤维缠结（NFT）。两者中，NFT是 与认知能力下降、神经元丧失和痴呆症的关系比斑块更密切， FTD模型与AD以及其他tau蛋白病的相关性。 有证据表明，可溶性细胞外形式的tau蛋白，而不是细胞内的神经元缠结， （NFT），可能是神经元功能障碍和细胞死亡的触发因素。实验将比较移植 将来自表达eGFP的tau缺失小鼠和表达小鼠tau的小鼠的神经球植入新生儿 表达相当水平的人突变型或野生型tau的rTg（tauP 301）和rTg（tauwt）小鼠，和 跟踪细胞存活，分化成神经元，并通过移植的后代形成突触 细胞除了解决内源性tau蛋白表达是否是细胞凋亡所必需的问题之外， 将评估细胞外tau聚集体的有害作用、丢失的宿主神经元的替代。 该项目将解决来自rTg（tauP 301 L）神经球的神经元是否发育的问题。 tau蛋白病以及tau蛋白病的传播是否受到tau蛋白一级结构不匹配的影响 移植物和宿主将开发完善的方法和工具，以促进干细胞的应用 移植，以了解疾病机制;这些应该证明有价值的超越这一具体 项目