UC Irvine AD Translational Center for Disease Model Resources

加州大学欧文分校 AD 疾病模型资源转化中心

基本信息

批准号：
10250340
负责人：
FRANK M LAFERLA
金额：
$ 280.32万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250340
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Antibodies Behavior Biological Biological Markers Brain CRISPR/Cas technology Cells Clinic Clinical Cognition Cryopreservation Data Dependence Development Diagnosis Disease Disease model Elderly Environmental Risk Factor Epigenetic Process Face Failure Functional Imaging Gene Expression Generations Genes Genetic Genetic Polymorphism Goals Hippocampus (Brain)Human Image Individual Intelligence Lasers Medical Methodology Methods Modeling Molecular Molecular Conformation Mus Mutation Neurodegenerative Disorders Neurons Pathology Penetrance Persons Phenotype Physiological Plasma Pre-Clinical Model Preclinical Testing Prevention Preventive therapy Preventive treatment Protocols documentation Reagent Regulator Genes Reproducibility Research Research Personnel Resources Risk Risk Factors Rodent Model Sampling Scanning Site Societies Technology Testing The Jackson Laboratory Therapeutic Time Translating Validation base behavioral phenotyping biomarker development cellular pathology clinical application disorder prevention drug development embryonic stem cell familial Alzheimer disease genome wide association study health economics homologous recombination human tissue improved innovation insight lipidomics metabolomics molecular pathology mouse model next generation novel novel therapeutics optimism overexpression patch clamp pre-clinical preclinical efficacy premature prevent repository research clinical testing restoration socioeconomics success tau Proteins therapeutic evaluation transcriptome sequencing

项目摘要

Project Abstract Alzheimer's disease (AD) is currently an incurable neurodegenerative disease that affects over 35 million people worldwide, including 5.4 million individuals in the USA with a new case diagnosed every minute. Over the past two decades, one of the most significant developments in the AD research field has been the generation of mouse models of AD. Although these have provided significant insight into the mechanism of AD, the findings have not yet translated into the development of any new disease-modifying therapies for the human condition. Moreover, there is concern about the discordance of treating AD in people versus mice, which may be due the incomplete modeling of the disease in mice. Along these lines, all of the currently available models are based on the rarer autosomal dominant form of the disease, whereas the majority of AD cases are sporadic, whose onset may still be influenced by genetics that display reduced penetrance compared to the autosomal dominant cases. Hence, there is an urgent need to develop the next generation of mouse models that have high face, construct, and translational validity, which means these models should be more closely aligned with sporadic AD (sAD). Over the past several years, the facility of GWAS has produced a rapid expansion in the list of risk factor genes that are associated with sAD. Here we propose to use a transdisciplinary/team approach to develop the next generation of mouse models that model sAD so that they can be used for preclinical therapeutic testing. Our strategy is to use our recently developed humanized wild- type APPKI mouse as the platform for introducing human tau, followed by other GWAS-identified risk polymorphisms that enhance the risk of developing sAD. We propose to develop the next generation of AD preclinical mouse models using the latest innovations in gene editing technology (CRISPR/Cas9 technology) to produce new mouse models that more accurately represent sAD. We will phenotype the mice using state-of- the-art quantitative methodology and make direct comparisons to the human condition and capitalize on novel reagents that have been developed at UCI, including unique conformation specific antibodies that identify multiple distinct forms of pathology. We will determine gene expression changes via RNA-seq and epigenetic disruptions, alterations in neuronal connectivity in hippocampal circuits via whole-cell patch clamping combined with laser scanning photostimulation, as well as LTP, behavior and cognition, and longitudinal functional imaging. We will also conduct biomarker development by performing plasma lipidomic and metabolomic analyses. We will distribute all data in an expeditious and accessible form for dissemination and will provide detailed protocols for characterization of the models for the field. Lastly, we have established an exciting partnership with The Jackson Laboratory to conduct second site validation of observed phenotypes and to re- derive, cryopreserve and distribute all new animal models so that they can be widely distributed to investigators in the field. Achieving these goals will be transformative for the AD research field.

项目摘要阿尔茨海默氏病（AD）目前是一种无法治愈的神经退行性疾病，影响超过3500万全球人，包括美国540万个人，每分钟都被诊断出一个新病例。超过在过去的二十年中，广告研究领域最重要的发展之一是 AD的鼠标模型的产生。尽管这些为AD机理提供了重大的见解，但这些发现尚未转化为开发任何新的疾病改良疗法人类状况。此外，人们担心在人与老鼠中对待广告的不一致，这可能是由于小鼠疾病的不完全建模。沿着这些路线，所有目前可用的模型基于疾病的稀有常染色体显性形式，而大多数AD 病例是零星的，其发作可能仍会受到遗传学的影响，这些遗传学显示出降低的渗透率与常染色体显性病例相比。因此，迫切需要发展下一代具有高面，构造和翻译有效性的鼠标模型，这意味着这些模型应该是与零星的AD（SAD）更紧密地对齐。在过去的几年中，GWAS的设施产生了与SAD相关的危险因素基因列表的快速扩展。在这里，我们建议使用跨学科/团队的方法开发下一代鼠标模型，以模拟SAD，以便他们可用于临床前治疗测试。我们的策略是使用我们最近开发的人性化野生键入Appki鼠标作为引入人类的平台，然后是其他GWAS识别风险多态性增强了发展悲伤的风险。我们建议开发下一代广告使用基因编辑技术（CRISPR/CAS9技术）的最新创新的临床前小鼠模型产生新的鼠标模型，更准确地代表SAD。我们将使用最新的小鼠表型 ART定量方法论，并直接与人类状况进行比较并利用新颖在UCI开发的试剂，包括识别的独特构象特定抗体多种不同的病理形式。我们将通过RNA-Seq和表观遗传来确定基因表达变化通过全细胞贴剂夹具组合的破坏，海马电路中神经元连通性的改变使用激光扫描光刺激以及LTP，行为和认知以及纵向功能成像。我们还将通过进行血浆脂质组和代谢组来进行生物标志物开发分析。我们将以迅速且易于访问的形式分发所有数据以进行传播，并将提供详细的协议，用于表征该领域的模型。最后，我们建立了一个令人兴奋的与杰克逊实验室的合作伙伴关系，对观察到的表型进行第二个现场验证，并重新进行得出，冷冻水果和分发所有新动物模型，以便将它们广泛分布到该领域的调查人员。实现这些目标将对广告研究领域具有变革性。