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：
8741917
负责人：
JORGE A BUSCIGLIO
金额：
$ 20.25万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741917
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 Glycogen Synthase Kinase 3 Goals Hereditary Disease Hippocampus (Brain)Homeostasis Human Impaired cognition Institutes Lead Lesion Link London Mediating Messenger RNA Microvascular Dysfunction 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 Vascular Diseases amyloid peptide amyloid precursor protein processing cell type cerebrovascular cohort disease mechanisms study disease phenotype end stage disease endothelial dysfunction 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

DESCRIPTION (provided by applicant): 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 peptide 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.

描述（由适用提供）：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患者的可行神经元的生成具有重要作用。这项技术对于创建体外模型来研究相关的人类细胞类型的病理生理学具有巨大的希望，原本是无法获得的。家族性的英国和丹麦痴呆症（分别为FBD和FDD）是常染色体的主要疾病，与阿尔茨海默氏病（AD）的许多临床和神经病理学特征非常相似，包括淀粉样蛋白淀粉样蛋白和淀粉样夹型病变，宽性脑膜状肿瘤性和神经性的肌化和神经性的异性症和神经性变性性变性，来自广告中的人。 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 peptide could trigger similar neuropathological changes leading to the same scenario: CAA-related microvascular dysfunction, neuronal loss and dementia.这就是这些家庭疾病构成有望更好地了解淀粉样蛋白在疾病发病机理复杂机制中的作用的替代范式。鉴于AD，FBD和FDD之间的许多临床和神经病理学相似性，我们建议I）生成和表征来自来自FBD和FBD患者同类的真皮成纤维细胞的IPSC系列，以及通过对非疾病的非疾病兄弟姐妹的研究，使用重复的MRNA Transfections a Sa Sa Safectrient a Sa Safecrient a Sa safe， ii）进一步区分通过良好的形态学，分子和生物学标准，新近生成的IPSC分为可行和功能性神经元和内皮细胞。我们预计这些IPSC衍生的成熟细胞将构成出色的候选者，以研究与FBD和FDD疾病表型相关的特定分子和临时方面。 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相关的血脑屏障功能障碍和微生物诊所的发展，随着神经血管单位和认知障碍的变化。该提案代表了纽约大学医学院和加利福尼亚大学尔湾分校的研究人员的合作努力，并以参与研究人员的完整专业知识以及他们对脑淀粉样蛋白疾病的分子发病机理的长期兴趣的建立。