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: 10045725
• 负责人: RICKI J COLMAN
• 金额: $ 34.88万
• 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/10045725
• 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; 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.

尽管数十年来，尽管存在于生物医学研究中，但普通的摩尔摩斯特（Callithrix jacchus）已在生物医学研究中使用，但缺乏关键工具（专门开发和验证了用于该物种的工具），这阻碍了进一步的进一步进展。在过去的十年中，Marmoset模型的普及急剧增加，这在很大程度上促成了其针对衰老，神经科学以及转基因和基因组编辑的研究效用。许多因素使该物种成为一个有吸引力的模型系统，包括它们与人类的遗传和身体相似性，相对较短的寿命，高生育能力，快速发展，小规模和类似人类的社会结构。重要的是，快速的生活史和高繁殖力的marmosets使它们成为转基因应用（例如阿尔茨海默氏病）（AD）的引人注目的模型，在非人类灵长类动物中比在啮齿动物模型中更合适。拟议的研究的目的是通过解决目前阻碍发展的几个主要差距，从而显着提高普通摩尔马斯群岛作为衰老模型的效用。我们选择将精力集中在与能源代谢，感染，神经退行性和脆弱性有关的生物标志物的发展上。在Marmoset老化模型的广泛应用方面，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，我们将使用新工具来测试我们的整体假设，即常见的摩尔果会显示出与年龄相关的炎症性张力差异，从而增加了代谢性和神经退行性疾病易感性，并且类似于人类衰老。为了解决这些确定的差距并证明我们的整体假设，我们提出了三个具体目标。目标1：开发低体积的能量调节，感染和神经变性的生物标志物。使用最先进的技术，我们将针对能源代谢，感染和神经变性研究的关键较高兴趣领域中的普通摩尔果明确开发和验证低容量测定法。目标2：开发与年龄相关感染的生物标志物以及β-淀粉样蛋白和tau在公共果果中的积累的生物标志物。尽管常见的果果是与年龄相关的神经退行性疾病的非常有前途的模型，但在该物种中尚未测试用于感染和神经退行性疾病（例如AD）的PET放射性疾病。我们建议通过评估F18-FEPPA注射F18-FEPPA，以及分别用于β-淀粉样蛋白和Tau的C11-PIB和F18-MK6240，以纠正Common Marmoset。目标3：开发一个常见的摩尔果特异性脆弱指数，以评估生物学与年代年龄。我们建议利用现有数据来开发一种常见的Marmoset特定脆弱指数，该指数可在广泛的研究中使用，以确定生物学年龄和治疗/干预措施的影响。鉴于对本提案中我们解决的领域的老化研究具有广泛的影响，我们相信通过这些目标获得的知识和技术将对普通Marmoset老化模型的实用性产生深远的影响。