Modeling Alzheimer's Disease Related Dementias in the Marmoset

模拟狨猴中与阿尔茨海默病相关的痴呆症

基本信息

批准号：
10705182
负责人：
KUO-FEN LEE
金额：
$ 91.47万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705182
关键词：
Acceleration Aging Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Amyotrophic Lateral Sclerosis Apolipoprotein E Apolipoproteins Behavioral Biochemical Blood - brain barrier anatomy Blood Vessels Body Size Brain Breeding C9ORF72 CRISPR/Cas technology Callithrix Central Nervous System Cognitive Complex Craniocerebral Trauma Dementia Development Dimensions Disease Disease Progression Doxycycline Environment Etiology Event Functional Magnetic Resonance Imaging Genes Genetic Goals Homeostasis Housekeeping Human Immunologic Receptors Infection Inflammatory Response Lewy Body Dementia Ligands Link Longevity Macrophage Magnetic Resonance Imaging Maintenance Mammals Mediating Metabolism Microglia Modeling Molecular Molecular Disease Mus Mutation Neurons Parkinson Disease Pathologic Pathology Pathway interactions Peptides Personal Satisfaction Phase Phenotype Play Positron-Emission Tomography Preclinical Testing Primates Process Research Risk Factors Role Series Signal Induction Signal Pathway Signal Transduction Structure Syndrome TREM2 gene Testing Time Transgenes Transgenic Organisms Variant Vascular System apolipoprotein E-4 cell type clinical diagnosis cognitive testing diagnostic tool early onset fluorodeoxyglucose positron emission tomography frontotemporal degeneration human disease immune function inducible gene expression metabolic fitness mixed dementia mouse model mutant neuroimaging neuroinflammation neuron loss neuropathology neuroprotection non-genetic nonhuman primate null mutation operation prevent promoter protein TDP-43 reproductive response screening social success therapeutic candidate therapeutic evaluation therapeutic target tool transgene expression translational neuroscience vascular cognitive impairment and dementia

项目摘要

Abstract The long-term goal of this project is to model Alzheimer's Disease related dementias (ADRD) in longer-living mammals. These multi-dimensional mammalian ADRD models, including frontotemporal degeneration (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and mixed etiology dementias, are aimed at informing human ADRD across the disease-relevant stages and serve as tools to interrogate disease mechanisms and identify therapeutic targets. ADRD develops as a result of a complex series of events that take place in the brain over a long period of time—the prodromal phase can last 10-20 years in humans—before dementia is clinically diagnosed. Understanding this EARLY stage will be critically important for developing diagnostic tools (e.g., neuroimaging) and for screening compounds to prevent or modify disease progression in humans. A variety of ADRD mouse models have been developed to advance research into the underlying molecular and cellular mechanisms, to identify therapeutic targets, and to test therapeutic candidates. While existing ADRD mouse models have enabled progress toward each of these objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular, cellular, behavioral and cognitive pathology observed in typical dementias. Several lines of evidence suggest that marmosets have emerged as a non-human primate model for both basic and translational neuroscience to bridge the gap between mice and humans. First, marmosets and humans have very similar complexity in brain structures, cognitive/social behavioral repertoires, metabolisms and immune functions. Second, as compared to other primates, it is highly economical and scalable for understanding brain functions and preclinical tests because they have a short lifespan, small body size, and high reproductive power. Finally, a set of gene editing tools is available to generate various types of genetically modified marmosets. Several lines of evidence led us to elucidate the role of the triggering receptor expressed on myeloid cells 2 (TREM2) pathways in ADRD. First, homozygous TREM2 null mutations have been linked to a recessive early-onset dementia syndrome called Nasu–Hakola disease. Several TREM2 variants are pathologic to FTD and a major risk factor/modifier for AD, Parkinson's disease, and amyotrophic lateral sclerosis (see https://www.alzforum.org/mutations/trem2). TREM2 mutation precipitates changes in vascular changes and blood brain barrier damages and may contribute to VCID. Second, microglia have emerged as a key cell type in the maintenance of central nervous system homeostasis, for which TREM2 mediates multiple critical signaling pathways. Third, aging is a major risk factor for ADRD. Decreased TREM2 expression during aging may accelerate ADRD development. Taken together , TREM2 is poised to influence neuronal and vascular systems associated with the development of multiple forms of ADRD. To elucidate the role of TREM2 in ADRD, different genetically modified marmosets will be generated and characterized.

抽象的该项目的长期目标是在长寿者中模拟阿尔茨海默病相关痴呆症 (ADRD) 这些多维哺乳动物 ADRD 模型，包括额颞叶变性 (FTD)、路易体痴呆 (LBD)、血管性认知障碍和痴呆 (VCID) 以及混合性痴呆病因学痴呆症，旨在告知人类 ADRD 跨越疾病相关阶段，并作为探究疾病机制并确定 ADRD 治疗靶点的工具。大脑在很长一段时间内发生的一系列复杂事件——前驱期可以持续人类需要 10-20 年——在临床诊断痴呆症之前，了解这一早期阶段。对于开发诊断工具（例如神经成像）和筛选化合物至关重要已开发出多种 ADRD 小鼠模型来预防或改变疾病进展。研究潜在的分子和细胞进展机制，以确定治疗靶点，并虽然现有的 ADRD 小鼠模型已经在这些方面取得了进展。目标，迄今为止可用的那些并没有概括分子的全谱和复杂性，一些证据表明，在典型痴呆症中观察到的细胞、行为和认知病理学。狨猴已成为基础神经科学和转化神经科学的非人类灵长类动物模型首先，狨猴和人类在复杂性方面非常相似。大脑结构、认知/社会行为、新陈代谢和免疫功能。与其他灵长类动物相比，它对于理解大脑功能和临床前测试，因为它们寿命短、体型小、繁殖能力高。一套基因编辑工具可用于生成多种类型的转基因狨猴。大量证据使我们阐明了骨髓细胞 2 上表达的触发受体 (TREM2) 的作用首先，纯合 TREM2 缺失突变与隐性早发性遗传相关。称为 Nasu-Hakola 病的痴呆症综合征。一些 TREM2 变异对 FTD 具有病理性，也是一种主要疾病。 AD、帕金森病和肌萎缩侧索硬化症的危险因素/调节因素（参见 https://www.alzforum.org/mutations/trem2）。其次，小胶质细胞已成为一种关键细胞类型。在维持中枢神经系统稳态中，TREM2 介导多个关键的第三，衰老是ADRD的主要危险因素。综合起来可能会加速 ADRD 的发展。 , TREM2 有望影响神经和血管与多种形式的 ADRD 发展相关的系统为了阐明 TREM2 在 ADRD 中的作用，将产生不同的转基因狨猴并对其进行表征。