Specific Pathogen Free Baboon Research Resource (SPFBRR) - Administrative Supplement (Epigenetic)

无特定病原体狒狒研究资源 (SPFBRR) - 行政补充（表观遗传学）

• 批准号: 10284289
• 负责人: Joe H. Simmons
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284289
• 关键词: 19 year old; Acceleration; Administrative Supplement; Age; Aging; Alzheimer' s Disease; Amyloid Proteins; Animal Model; Behavior; Behavioral; Biological Markers; Breeding; Cerebrospinal Fluid; Chronic Disease; Chronology; DNA Methylation; Data; Development; Diabetes Mellitus; Disease; Elderly; Epigenetic Process; Experimental Animal Model; Experimental Models; Funding; Genome; Individual; Intervention; Investigation; Life; Lymphocyte; Modeling; Morbidity - disease rate; Mothers; Motor; Neuropathy; Neurosciences; Nurseries; Papio; Pathology; Performance; Physiology; Plasma; Population; Process; Research; Resources; Risk Factors; Sampling; Site; Testing; Time; University of Texas M D Anderson Cancer Center; Virus; age related; aged; early life stress; germ free condition; molecular marker; mortality; neutrophil; nonhuman primate; parent grant; phenotypic biomarker; stressor; tau Proteins; walking speed

Project Summary/Abstract Epigenetic age is a new, robust biomarker of aging that has outperformed other molecular and phenotypic biomarkers of aging in predicting morbidity and mortality. Epigenetic age is calculated using DNA methylation levels at specific sites in the genome to create a DNA methylation clock (DMC). The DMC is then used to find the deviation between an individual’s epigenetic age and chronological age, which determines whether the individual shows age-acceleration, which has been implicated in a host of age-related diseases, including AD/ADRD. However, DMCs have not been developed for baboons, a commonly-used animal model for various aging-related diseases. Given that baboons show hallmarks of AD neuropathy, there is a need for further development of the baboon as a model for aging and AD. The University of Texas MD Anderson Cancer Center (MDACC) is growing and maintaining the world’s only adventitious virus-free baboon breeding colony (Specific Pathogen Free Baboon Research Resource). Therefore, the proposed administrative supplement to the P40 parent grant is requesting additional funds to examine baboons as an animal model for accelerated aging, and to establish baseline data for AD and aging-associated biomarkers to increase the utility of this research resource. In Aim 1, we propose using DNA methylation levels to create a baboon-specific DMC in 175 mother- and nursery-reared baboons aged 3-19 years old. We will use this DMC to predict chronological age, and the discrepancy between chronological and epigenetic age will be used to identify individuals that show age acceleration. Additionally, given that nursery-rearing (an early life stressor) is associated with a host of deleterious effects on behavior and physiology, we will investigate the relationship between nursery-rearing and accelerated aging. If this indeed accelerates aging, nursery-reared baboons would serve as an important experimental animal model of early life stress, aging, and the development of AD. In Aim 2, we will establish baseline levels of AD/ADRD biomarkers, as well as determine whether age acceleration in this baboon model is associated with said biomarkers. Multiplexed Luminex biomarkers will include plasma levels of an 18-plex neuroscience panel including AD/ADRD biomarkers such as amyloid and tau proteins, a 10-plex of diabetes biomarkers, neutrophil to lymphocyte ratio (NLR), as well as behavioral markers (i.e., walking speed and motor performance), at two time points in the 175 baboons from Aim 1. We will also examine levels of these biomarkers in cerebrospinal fluid in a subset of 20 geriatric baboons at two time points as well (15 years and older).The proposed project will create a better-defined research resource under the P40 parent grant by 1) creating an experimental model of accelerated aging that can be used to test interventions in controlled settings; and 2) establish baselines of AD/ADRD biomarkers in the baboon sample, thereby increasing characterization of the population and opening avenues for longitudinal AD/ADRD research.

项目摘要/摘要 表观遗传时代是一种新的，可靠的衰老生物标志物，它的表现优于其他分子和表型 衰老的生物标志物预测发病率和死亡率。使用DNA甲基计算表观遗传年龄 基因组中特定位点的水平以创建DNA甲基化时钟（DMC）。然后使用DMC查找 个体的表观遗传年龄与年龄年龄之间的离职，这决定了是否是否 各个显示年龄加速器，这是在许多与年龄有关的疾病中暗示的，包括 广告/adrd。但是，尚未开发DMC的狒狒，狒狒是一种常用的动物模型 与衰老有关的疾病。鉴于狒狒表现出AD神经病的标志，需要进一步 开发狒狒作为衰老和AD的典范。德克萨斯大学医学博士安德森癌症 中心（MDACC）正在增长和维护世界上唯一的唯一不定病毒的狒狒繁殖殖民地 （特定的无病原体研究资源）。因此，提议的行政补充 P40父母赠款正在要求额外的资金检查狒狒作为一种加速的动物模型 衰老，并为AD和与衰老相关的生物标志物建立基线数据，以提高其效用 研究资源。在AIM 1中，我们建议使用DNA甲基化水平在IN中创建狒狒特异性DMC 175岁的母亲和托儿所的狒狒3-19岁。我们将使用此DMC预测时间顺序 年龄以及年代和表观遗传年龄之间的差异将用于识别个人 显示年龄加速。此外，鉴于育儿（早期生活压力源）与宿主有关 对行为和生理学的有害影响，我们将研究育苗的关系 和加速衰老。如果这确实加速了衰老，育苗的狒狒将成为重要的 早期生活压力，衰老和AD发展的实验动物模型。在AIM 2中，我们将建立 AD/ADRD生物标志物的基线水平，并确定该狒狒模型中的年龄加速 与上述生物标志物有关。多路复用Luminex生物标志物将包括18-PLEX的等离子体水平 神经科学面板包括AD/ADRD生物标志物，例如淀粉样蛋白和Tau蛋白，10个糖尿病 生物标志物，中性粒细胞与淋巴细胞比（NLR）以及行为标记（即步行速度和运动 性能），在AIM 1的175次狒狒中的两个时间点。我们还将检查其中的水平 脑脊液中的生物标志物在两个时间点也有20个老年狒狒的子集（15年， 较旧的）。拟议的项目将根据P40父母的赠款创建一个更好定义的研究资源。 创建一个加速衰老的实验模型，可用于测试受控的干预措施 设置; 2）在狒狒样品中建立AD/ADRD生物标志物的基准，从而增加 人口的表征和开放纵向AD/ADRD研究的途径。