Enhancing the marmoset aging model through biomarker development

通过生物标志物开发增强狨猴衰老模型

• 批准号: 10263239
• 负责人: RICKI J COLMAN
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263239
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Area; Biological; Biological Assay; Biological Markers; Biological Models; Biology of Aging; Biomedical Research; Brain imaging; Callithrix; Callithrix jacchus jacchus; Categories; Chronology; Data; Deposition; Development; Disease; Disease susceptibility; Energy Metabolism; Evaluation; Fertility; Fostering; Genetic; Goals; Human; Immunoassay; Inflammaging; Inflammation; Inflammatory; Insulin; Intervention; Investigation; Knowledge; Leptin; Light; Longevity; Macaca; Metabolic Diseases; Modeling; Morbidity - disease rate; Nerve Degeneration; Neurodegenerative Disorders; Neurosciences; Peptides; Phenotype; Physiological; Population; Positron-Emission Tomography; Process; Recording of previous events; Regulation; Research; Research Project Grants; Risk Factors; Rodent; Rodent Model; Techniques; Testing; Thinking; Transgenic Model; Transgenic Organisms; Validation; abeta accumulation; adiponectin; age effect; age related; age related neurodegeneration; aging population; assay development; base; biomarker development; circulating biomarkers; cytokine; energy balance; experience; frailty; functional decline; genome editing; glucagon-like peptide 1; human disease; human old age (65+); imaging biomarker; in vivo; indexing; interest; life history; neurofilament; nonhuman primate; novel; radioligand; social structure; tau Proteins; tau aggregation; tool; treatment effect; treatment strategy

Although the common marmoset (Callithrix jacchus) has been used in biomedical research for decades, the lack of crucial tools, specifically developed and validated for use in this species, has hampered further advances. Within the last 10 years, popularity of the marmoset model has increased dramatically, prompted to a large degree by realization of their utility for research focused on aging, neuroscience and transgenic and genomic editing. Many factors make this species an attractive model system including their genetic and physiological similarity to humans, relatively short lifespan, high fertility, rapid development, small size and human-like social structure. Importantly, the rapid life history and high fecundity of marmosets make them a compelling model for transgenic applications such as for Alzheimer’s disease (AD), that are much more appropriate in a nonhuman primate than in a rodent model. The goal of the proposed study is to significantly increase the utility of the common marmoset as a model of aging by addressing several of the major gaps currently hampering development. We have chosen to focus our efforts on the development of biomarkers related to energy metabolism, inflammation, neurodegeneration and frailty; areas that will provide the highest return in terms of broad application of the marmoset aging model. Following successful development and validation of our biomarkers, we will use our new tools to test our overall hypothesis that common marmosets show age-related differences in inflammatory tone that increase metabolic and neurodegenerative disease susceptibility and resembles human aging. To address these identified gaps and prove our overall hypothesis we propose three Specific Aims. Aim 1: To develop low volume circulating biomarkers of energy regulation, inflammation and neurodegeneration. Using state-of-the-art techniques, we will develop and validate low volume assays explicitly for common marmosets in the crucial high interest areas for aging research of energy metabolism, inflammation and neurodegeneration. Aim 2: To develop in vivo brain imaging biomarkers of age-related inflammation and accumulation of β amyloid and tau in common marmosets. Although the common marmoset is a very promising model of age-related neurodegenerative diseases, PET radioligands for inflammation and neurodegenerative disorders such as AD have not been tested in this species. We propose to rectify this by evaluating F18-FEPPA for inflammation and C11-PiB and F18-MK6240, for β amyloid and tau, respectively, for the common marmoset. Aim 3: To develop a common marmoset-specific frailty index to assess biological versus chronological age. We propose to utilize existing data to develop a common marmoset-specific frailty index that can be used across a broad range of studies to determine biological age and effect of treatments/interventions. Given the broad implications to aging research of the areas we address in this proposal, we are confident that the knowledge and techniques garnered through these aims will have far-reaching impact on the utility of the common marmoset aging model.

虽然普通狨猴（Callithrix jacchus）已被用于生物医学研究数十年，但缺乏专门开发和验证用于该物种的关键工具，阻碍了进一步的进展。在过去的10年里，狨猴模型的普及程度急剧增加，这在很大程度上是由于它们在衰老、神经科学、转基因和基因组编辑等研究中的应用。该物种具有与人类相似的遗传和生理特征、相对较短的寿命、较高的繁殖力、快速的发育、较小的体型和类似人类的社会结构等特点。重要的是，狨猴的快速生活史和高繁殖力使它们成为转基因应用的引人注目的模型，如阿尔茨海默病（AD），这在非人类灵长类动物身上比在啮齿动物身上更合适。该研究的目标是通过解决目前阻碍发展的几个主要差距，显著提高普通狨猴作为衰老模型的效用。我们选择专注于开发与能量代谢、炎症、神经变性和虚弱相关的生物标志物；就狨猴衰老模型的广泛应用而言，将提供最高回报的领域。在成功开发和验证我们的生物标志物之后，我们将使用我们的新工具来测试我们的总体假设，即普通狨猴在炎症音调方面表现出与年龄相关的差异，从而增加代谢和神经退行性疾病的易感性，类似于人类衰老。为了解决这些已确定的差距并证明我们的总体假设，我们提出了三个具体目标。目的1：开发能量调节、炎症和神经变性的低容量循环生物标志物。使用最先进的技术，我们将在能量代谢、炎症和神经变性等衰老研究的关键高兴趣领域开发和验证普通狨猴的低体积分析。目的2：在普通狨猴中开发与年龄相关的炎症和β淀粉样蛋白和tau蛋白积累的体内脑成像生物标志物。虽然普通狨猴是一种非常有前途的与年龄相关的神经退行性疾病的模型，但PET放射配体治疗炎症和神经退行性疾病（如AD）尚未在该物种中进行过测试。我们建议通过评估F18-FEPPA对炎症的影响以及C11-PiB和F18-MK6240对普通狨猴的β淀粉样蛋白和tau蛋白的影响来纠正这一问题。目的3：开发一种常见的狨猴特异性脆弱指数来评估生物年龄与实足年龄。我们建议利用现有数据开发一种常见的狨猴特异性脆弱指数，该指数可用于广泛的研究，以确定生物年龄和治疗/干预的效果。鉴于我们在本提案中所涉及的领域对衰老研究的广泛影响，我们相信通过这些目标获得的知识和技术将对普通狨猴衰老模型的效用产生深远的影响。