iPSC from British and Danish dementias: new discovery tools for brain amyloidoses

来自英国和丹麦痴呆症的 iPSC：大脑淀粉样变性的新发现工具

基本信息

批准号：
8652006
负责人：
JORGE A BUSCIGLIO
金额：
$ 26.03万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652006
关键词：
APP gene Abrus Affect Alzheimer&apos s Disease Amyloid Amyloidosis Animal Model Autopsy Biological Biopsy Blood - brain barrier anatomy Blood Vessels Brain British California Cell Death Cell Line Cell model Cells Cerebral Amyloid Angiopathy Cerebrum Clinical Collaborations Complex DNA Dementia Denmark Deposition Dermal Development Disease Down Syndrome Employee Strikes Endothelial Cells Endothelium Exhibits Familial disease Fibroblasts Functional disorder Future Generations Genes Goals Hereditary Disease Hippocampus (Brain)Homeostasis Human Impaired cognition Institutes Lead Lesion Link London Mediating Messenger RNA Modeling Molecular Mus Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neurology Neuronal Dysfunction Neurons New York Pathogenesis Pathologic Processes Pathway interactions Patients Phenotype Pluripotent Stem Cells Preclinical Drug Evaluation Presenile Alzheimer Dementia Process Production Protein Precursors RNA Rare Diseases Regulation Reporting Research Research Personnel Role Siblings Skin Somatic Cell Synapses Technology Tissues Transfection Transgenic Animals Universities University Hospitals amyloid peptide amyloid precursor protein processing cell type cerebrovascular cohort disease mechanisms study disease phenotype end stage disease in vitro Model induced pluripotent stem cell innovation interest medical schools nervous system disorder neurofibrillary tangle formation neuron loss neurovascular unit novel public health relevance relating to nervous system secretase tau Proteins tau aggregation tool

项目摘要

Reprogramming of primary dermal fibroblasts into induced pluripotent stem cells (iPSCs) has recently proven to be instrumental for the generation of viable neurons derived from patients with neurodegenerative disorders. This technology holds tremendous promise for the creation of in vitro models to study disease pathophysiology in relevant human cell types that would otherwise be impossible to obtain. Familial British and Danish dementias (FBD and FDD, respectively) are autosomal dominant conditions that closely resemble many clinical and neuropathological features of Alzheimer's disease (AD) including parenchymal amyloid and pre- amyloid lesions, widespread cerebral amyloid angiopathy and neurofibrillary tangles morphologically and immunochemically indistinguishable from those in AD. Notably, the amyloid subunits isolated from FBD deposits -ABri- and FDD lesions -ADan- are structurally unrelated to the Alzheimer's A¿, a clear indication that different amyloid peptides could trigger similar neuropathological changes leading to the same scenario: CAA-related microvascular dysfunction, neuronal loss and dementia. Thus, these familial disorders constitute promising alternative paradigms to better understand the role of amyloid in the complex mechanisms of disease pathogenesis. In view of the many clinical and neuropathological similarities between AD, FBD and FDD, we are proposing i) to generate and characterize iPSC lines from dermal fibroblasts obtained from a cohort of FBD and FDD patients as well as from non-carrier siblings of both disorders using repetitive mRNA transfections, a safer non- DNA-integrating technology successfully used by the research team; and ii) to further differentiate the newly generated iPSCs into viable and functional neurons and endothelial cells characterized through well- established morphological, molecular and biological criteria. We anticipate that these iPSC-derived mature cells will constitute excellent candidates to study specific molecular and temporal aspects linked to FBD and FDD disease phenotypes. Moreover, they will have a broader impact in the field of neurodegenerative disorders, extending beyond these rare diseases into the field of AD, providing invaluable options for a better understanding of the mechanisms that modulate APP processing, A¿ homeostasis and the process of tau hyperphosphorylation, serving as alternative paradigms for high throughput drug screening platforms, and assisting with the identification of cross-talk pathways connecting CAA-associated blood brain barrier dysfunction and development of microhemorrhages with changes in the neurovascular unit and cognitive impairment. This proposal represents a collaborative effort from investigators of New York University School of Medicine and the University of California, Irvine and builds on the complementary expertise of the participating researchers and their long-standing interest in the molecular pathogenesis of cerebral amyloid disorders.

将原发性皮肤成纤维细胞重编程为诱导的多能干细胞（IPSC）最近已证明对产生来自神经退行性疾病的患者的生存神经元的生成有用。这项技术对于创建体外模型来研究疾病生理生理学具有巨大的希望在相关的人类细胞类型中，原本无法获得的人类细胞类型。家族英国和丹麦痴呆症（分别为FBD和FDD）是常染色体显性疾病，非常类似于许多阿尔茨海默氏病（AD）的临床和神经病理学特征，包括淀粉样蛋白淀粉样蛋白和前淀粉样蛋白病变，宽度脑淀粉样蛋白血管病和神经原纤维缠结在形态上和与AD中的人无法区分免疫化学。值得注意的是，从FBD中分离出的淀粉样蛋白亚基沉积物-Abri-和FDD病变-Adan-在结构上与阿尔茨海默氏症的a不相关，清晰指示不同的淀粉样蛋白宠物可能会引发类似的神经病理学变化，从而导致相同的情况：与CAA相关的微血管功能障碍，神经元丧失和痴呆症。那是这些家族障碍构成的有希望的替代范式更好地了解淀粉样蛋白在复杂机制中的作用疾病发病机理。鉴于AD，FBD和FDD之间的许多临床和神经病理学相似性，我们提出了I）从FBD和FDD的同类中获得的真皮成纤维细胞产生和表征IPSC线患者以及两种疾病的非载体兄弟姐妹都使用重复的mRNA转染，一种更安全的非 - 研究团队成功使用了DNA整合技术； ii）进一步区分新的通过良好表征建立的形态学，分子和生物学标准。我们预计这些IPSC衍生的成熟细胞将构成研究与FBD和FBD相关的特定分子和临时方面的出色候选者 FDD疾病表型。此外，它们将在神经退行性领域产生更大的影响疾病，将这些罕见疾病延伸到广告领域，提供了宝贵的选择了解调节应用程序处理，A稳态和TAU过程的机制高磷酸化，作为高通量药物筛查平台的替代范式，协助识别连接CAA相关的血脑屏障的串扰途径随着神经血管单位和认知变化的微视力障碍和开发损害。该建议代表了纽约大学医学院调查人员的合作努力加利福尼亚大学尔湾分校，并建立在参与的完整专业知识的基础上研究人员及其对脑淀粉样蛋白疾病的分子发病机理的长期兴趣。