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: 8911231
• 负责人: George A. Carlson
• 金额: $ 20.86万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911231
• 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; Health; 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; research study; synaptogenesis; tau Proteins; tau aggregation; tau expression; therapy development; tool

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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。中枢神经系统干细胞（CNS- sc）移植被吹捧为治疗阿尔茨海默病（AD）和其他退行性脑疾病的一种有前途的方法，这是有理由的，通过替代丢失的细胞或作为递送治疗剂的载体。中枢神经干细胞移植也可能为解剖疾病的过程和机制提供新的途径。该试点项目的广泛目标是评估和完善神经球移植作为解剖tau病理的致病机制和传播的工具。将探索两种范式：1)将来自未发病小鼠的含有神经球的CNS-SC移植到疾病模型中，以及2)将来自疾病模型的神经球移植到未发病小鼠中。这些初步研究的基础是表征良好的rTg(tauP301L)4510模型，用于治疗脑损伤性额颞叶痴呆（FTD）。AD的特征是细胞外淀粉样斑块和细胞内由聚集的tau蛋白组成的神经纤维缠结（nft）。其中，与斑块相比，nft与认知能力下降、神经元丧失和痴呆的关系更为密切，这表明FTD模型与阿尔茨海默病以及其他tau病的相关性。有证据表明，可溶性细胞外形式的tau，而不是细胞内神经原纤维缠结（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egfp表达tau null和小鼠tau表达小鼠的神经球移植到表达相当水平的人类突变型或野生型tau的新生rTg（tauP301）和rTg（tauwt）小鼠中，并跟踪细胞存活、神经元分化和突触形成