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.

项目总结/摘要 表观遗传年龄是一种新的，强大的衰老生物标志物，其表现优于其他分子和表型生物标志物。 衰老的生物标志物在预测发病率和死亡率。表观遗传年龄使用DNA甲基化计算 在基因组中的特定位点的水平，以创建一个DNA甲基化时钟（DMC）。然后使用DMC来查找 一个人的表观遗传年龄和实足年龄之间的偏差，它决定了是否 个体显示出衰老加速，这与许多与年龄有关的疾病有关，包括 AD/ADRD。然而，尚未为狒狒开发DMC，狒狒是各种疾病的常用动物模型。 与衰老有关的疾病。鉴于狒狒显示出AD神经病变的特征，需要进一步研究。 狒狒作为衰老和AD模型的发展。德克萨斯大学医学博士安德森癌症 中心（MDACC）正在发展和维护世界上唯一的无外源病毒狒狒繁殖群 （Specific Pathogen Free Baboon Research Resource）因此，拟议的行政补充 P40父母补助金要求额外的资金，以检查狒狒作为动物模型， 衰老，并建立AD和衰老相关生物标志物的基线数据，以增加其效用。 研究资源。在目标1中，我们提出使用DNA甲基化水平来创建狒狒特异性DMC， 175只3-19岁的母亲和托儿所饲养的狒狒。我们将使用此DMC来预测时间顺序 年龄，以及实足年龄和表观遗传年龄之间的差异将用于识别 显示年龄加速。此外，鉴于托儿所养育（一种早期生活压力源）与宿主有关， 对行为和生理的有害影响，我们将调查托儿所养育之间的关系 加速老化。如果这真的加速了衰老，托儿所饲养的狒狒将成为一个重要的 实验动物模型的早期生活压力，老化，和AD的发展。在目标2中，我们将建立 AD/ADRD生物标志物的基线水平，以及确定该狒狒模型中的年龄加速是否 与所述生物标志物相关。多重Luminex生物标志物将包括18-plex生物标志物的血浆水平。 神经科学小组，包括AD/ADRD生物标志物，如淀粉样蛋白和tau蛋白，糖尿病的10重 生物标志物，中性粒细胞与淋巴细胞比率（NLR），以及行为标志物（即，行走速度和电机 在来自Aim 1的175只狒狒中，在两个时间点观察到了这一结果。我们还将研究这些水平 在两个时间点（15岁和15岁）， 拟议的项目将在P40母基金下创建一个更明确的研究资源， 创建加速老化的实验模型，可用于测试受控环境中的干预措施。 2）在狒狒样本中建立AD/ADRD生物标志物的基线，从而增加 人口的特点和纵向AD/ADRD研究的开放途径。