Enhancing the marmoset aging model through biomarker development

尽管常见的绒猴(Callithrix Jacchus)已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，绒猴模型的受欢迎程度急剧增加，这在很大程度上是因为人们意识到它们在专注于衰老、神经科学以及转基因和基因组编辑的研究中的效用。许多因素使该物种成为一个有吸引力的模式系统，包括它们与人类在遗传和生理上的相似性、相对较短的寿命、高生育率、快速发展、体型较小和类似人类的社会结构。重要的是，绒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，例如阿尔茨海默病(AD)，这在非人类灵长类动物中比在啮齿动物模型中更合适。拟议研究的目标是通过解决目前阻碍发展的几个主要差距，显着增加普通绒猴作为衰老模型的效用。我们选择将重点放在与能量代谢、炎症、神经退化和脆弱相关的生物标记物的开发上，这些领域将在广泛应用绒猴衰老模型方面提供最高的回报。在成功开发和验证我们的生物标记物后，我们将使用我们的新工具来测试我们的总体假设，即普通绒猴在炎症基调方面表现出与年龄相关的差异，这种差异增加了代谢和神经退行性疾病的易感性，并类似于人类的衰老。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，我们将开发和验证在能量代谢、炎症和神经退化等衰老研究的关键高兴趣领域中常见绒猴的低容量分析。目的2：建立与年龄相关的炎症和β、淀粉样蛋白和tau在普通绒猴体内蓄积的脑成像生物标志物。虽然常见的绒猴是一种非常有希望的与年龄相关的神经退行性疾病的模型，但用于炎症和神经退行性疾病(如AD)的PET放射性配体尚未在该物种中进行测试。我们建议通过评估F18-FEPPA是否存在炎症，以及C11-PIB和F18-MK6240是否存在β淀粉样蛋白和tau来纠正这一问题。目的3：开发一种通用的绒猴特有的脆弱指数来评估生物学年龄与时间年龄。我们建议利用现有的数据来开发一个共同的绒猴特有的脆弱指数，该指数可以在广泛的研究中使用，以确定生物年龄和治疗/干预的效果。鉴于本提案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常见的绒猴衰老模型的实用性产生深远影响。

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.