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：
10618761
负责人：
KUO-FEN LEE
金额：
$ 93.72万
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/10618761
关键词：
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 C9ORF72 CRISPR/Cas technology Callithrix Cognitive Complex Craniocerebral Trauma Dementia Development Disease Disease Progression Doxycycline Environment Etiology Event Functional Magnetic Resonance Imaging Genes Genetic Goals Homeostasis Housekeeping Human Immunologic Receptors Impaired cognition Infection Inflammatory Response Lewy Body Dementia Ligands Link Longevity Magnetic Resonance Imaging Maintenance Mammals Mediating Metabolism Microglia Modeling Molecular Molecular Disease Mus Mutation Neuraxis 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 Pathway Signal Transduction Structure Syndrome TREM2 gene Testing Time Transgenes Transgenic Organisms Variant Vascular System cell type clinical diagnosis cognitive testing diagnostic tool early onset fluorodeoxyglucose positron emission tomography frontotemporal degeneration human disease immune function inducible gene expression macrophage metabolic fitness mixed dementia mouse model mutant neuroimaging neuroinflammation neuron loss 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对老年痴呆症与痴呆症相关的痴呆症（ADRD）建模哺乳动物。这些多维哺乳动物ADRD模型，包括额颞变性（FTD）， Lewy身体痴呆（LBD），对认知障碍和痴呆（VCID）的血管贡献，以及混合病因学痴呆症旨在告知与疾病相关的阶段的人类ADRD，并作为询问疾病机制并确定治疗靶标的工具。由于长期在大脑中发生的一系列复杂事件 - 前阶段可以持续在临床上诊断出痴呆症之前，人类10 - 20年。了解这个早期阶段将是至关重要的是开发诊断工具（例如神经影像学）和筛选化合物至关重要预防或改变人类疾病的进展。已经开发了各种ADRD鼠标模型提高对潜在分子和细胞机制的研究，以鉴定治疗靶标的以及测试理论候选人。虽然现有的ADRD鼠标模型已启用了每个鼠标的进步目的，迄今为止可用的目标并未概括分子的全光谱和复杂性，典型痴呆症观察到细胞，行为和认知病理。几条证据表明 Marmoset已成为基本和转化神经科学的非人类私人模型弥合小鼠和人类之间的缝隙。首先，摩尔果和人类的复杂性非常相似大脑结构，认知/社会行为曲目，代谢和免疫功能。第二，as 与其他主要主要相比，它是高度经济的，可扩展的，可用于理解大脑功能和临床前测试是因为它们的寿命很短，体型较小和繁殖能力很高。最后，一个一组基因编辑工具可用于生成各种类型的一般修改的摩尔果。几行证据导致我们阐明了在髓样细胞2（TREM2）上表达的触发受体的作用 Adrd的途径。首先，纯合TREM2无效突变已与隐性早期发作有关痴呆综合征称为NASU – Hakola病。几种Trem2变体是FTD的病理学和主要的 AD，帕金森氏病和肌萎缩性侧面硬化症的危险因素/修饰符（请参阅 https://www.alzforum.org/mutations/trem2）。 Trem2突变会导致血管变化的变化和血脑屏障的损害可能会导致VCID。其次，小胶质细胞已成为关键细胞类型在维持中枢神经系统稳态的维持中，trem2介导了多个关键信号通路。第三，衰老是ADRD的主要危险因素。衰老期间的Trem2表达降低可能会加速ADRD的发展。一起，TREM2被中毒以影响神经元和血管与多种形式的ADRD相关的系统。为了阐明trem2在ADRD中的作用，将生成和表征不同的一般修改的摩尔果。