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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

尽管普通狨猴 (Callithrix jacchus) 已用于生物医学研究数十年，但由于缺乏专门开发和验证用于该物种的关键工具，在过去 10 年里阻碍了狨猴模型的进一步发展。显着增加，在很大程度上是由于意识到它们在衰老、神经科学、转基因和基因组编辑研究中的实用性，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生理相似性、相对较短的寿命、重要的是，狨猴的高繁殖力、快速发育、小体型和类似人类的社会结构，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），这更适合于人类。拟议研究的目标是通过解决目前阻碍发育的几个主要差距，显着提高普通狨猴作为衰老模型的效用。生物标志物与能量代谢、炎症、神经退行性变和虚弱相关；在狨猴衰老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后，我们将使用我们的新工具来测试我们的总体假设：普通狨猴在炎症方面表现出与年龄相关的差异，增加了代谢和神经退行性疾病的易感性，并且与人类衰老相似。为了解决这些已发现的差距并证明我们的总体假设，我们提出了三个具体目标 1：开发低容量循环生物标志物。我们将利用最先进的技术，在能量代谢、炎症和神经退行性衰老研究的关键领域中开发和验证普通狨猴的低检测体积。开发普通狨猴中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与年龄相关的神经退行性疾病的非常有前途的模型，但用于炎症和 PET 放射性配体。对于普通狨猴，我们尚未针对 AD 等神经退行性疾病进行测试，并分别针对炎症和 C11-PiB 和 F18-MK6240 进行纠正。开发一个常见的狨猴特异性衰弱指数来评估生物学年龄和实际年龄。我们建议利用现有数据开发一个常见的狨猴特异性衰弱指数。考虑到我们在本提案中讨论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具有广泛的意义。对普通狨猴衰老模型的实用性产生了深远的影响。