Development Project 2

开发项目2

• 批准号: 7646017
• 负责人: THOMAS COSTIN REGISTER
• 金额: $ 5.44万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646017
• 关键词: Abdomen; Activities of Daily Living; Adipocytes; Adipose tissue; Affect; Age; Aging; Animal Model; Animals; Area; Biochemical; Biological Markers; Blood specimen; Body Composition; Cells; Characteristics; Chronic Disease; Complement; Condition; Data; Depth; Development; Disease; Dual-Energy X-Ray Absorptiometry; Equilibrium; Fatty acid glycerol esters; Funding; Future; Genes; Goals; Health; Histologic; Histology; Human; Image; In Vitro; Infiltration; Inflammation; Inflammatory; Invasive; Link; Location; Longitudinal Studies; Macaca fascicularis; Mediator of activation protein; Metabolic; Modeling; Molecular; Monkeys; Muscle; Nature; Numbers; Obesity; Organ; Performance; Pericardial body location; Personal Satisfaction; Physical Function; Physiological; Production; Research; Research Personnel; Resources; Risk; Scanning; Signal Transduction; Skeletal Muscle; Specimen; Speed; Stromal Cells; Study models; Technical Expertise; Testing; Tissue Sample; Tissues; Triglycerides; Variant; Visceral; Walking; X-Ray Computed Tomography; adipokines; age related; attenuation; base; bioimaging; concept; density; disability; functional decline; improved; macrophage; mortality; nonhuman primate; subcutaneous; translational approach

d. SPECIFIC AIMS: Body composition and fat distribution, and the redistribution of fat with aging, are related to disability through increased risk of age-related diseases and impaired physical function. Non-invasive imaging of fat depots by computed tomography (CT) shows that the amount of fat in abnormal or ectopic locations, such as surrounding the visceral organs and within muscle, has adverse consequences on health and function. Beyond fat volume, our preliminary data indicate that adipose tissue density (as determined by CT signal attenuation) predicts mobility limitation and mortality, independent of total adiposity or fat location (see section f). However, unlike in skeletal muscle where CT attenuation is known to be indicative of greater triglyceride infiltration, virtually nothing is known regarding the nature and biologic basis of variation in CT attenuation in adipose tissue, providing us with an opportunity to explore this area using a reverse translational approach. We propose that higher fat density (e.g., higher CT attenuation) is due to a greater infiltration of inflammatory cells, which results in greater production of inflammatory mediators and, perhaps, reduced physical function. It is well known that fat depots are heterogenous in that they differ in metabolic function, as well as biochemical and cellular composition. There is location-specific variability in the number of stromal cells, preadipocytes, and inflammatory cells such as macrophages in fat. Much evidence suggests these depot-specific characteristics may contribute to age-related health problems; yet, the pathophysiological mechanisms by which different fat depots affect chronic disease and disability are not fully understood. Although it is possible to study molecular and metabolic characteristics of subcutaneous fat in humans, for obvious reasons, it is not feasible to invasively study deep subcutaneous, visceral, pericardial, or intra-muscular fat depots in humans. Thus, a reliable and valid animal model, with relevant application to changes in adiposity and associated health conditions with human aging, is needed to elucidate physiological and molecular differences between adipose tissue depots, factors underlying changes in fat distribution with age, and how these depot differences and fat distribution changes contribute to disabling chronic disease and declines in physical function with age. The overall goal of this Development Project is to incorporate and expand the use of the nonhuman primate resources at WFUSM for the study of human aging, especially for the study of regional adipose tissue characteristics and their link to aging-related health conditions. This will be done by testing specific hypotheses, both retrospectively (using stored specimens and bioimaging scans) and prospectively (using a longitudinal study), in cynomolgus monkeys as outlined below. The proposed studies will improve our understanding of the biologic basis of differential fat CT attenuation using this well-characterized nonhuman primate model of fat distribution and age-related disease, and will allow us to determine the nature and composition of adipose tissue at the histologic and molecular level as a complement to the imaging studies. Performing the in vitro and the imaging assessments of adipose tissue in tandem with inflammatory disease biomarkers and functional capacity will provide the necessary "proof-of-concept" data for establishing this animal as a research model with similarities to human aging for future use by OAIC investigators.

D.具体目标： 身体成分和脂肪分布，以及随着年龄的增长脂肪的重新分布，都与残疾有关 通过增加与年龄有关的疾病和身体功能受损的风险。非侵入性脂肪成像 通过计算机断层扫描（CT）显示，在异常或异位位置的脂肪量，如 在内脏器官周围和肌肉内，对健康和功能有不利影响。 除了脂肪体积，我们的初步数据表明，脂肪组织密度（由CT信号确定 衰减）预测活动受限和死亡率，与总肥胖或脂肪位置无关（见第节 （f）。然而，与骨骼肌不同的是，已知骨骼肌的CT衰减指示更高的甘油三酯 由于肿瘤的浸润性，关于肿瘤CT衰减变化的性质和生物学基础几乎一无所知。 脂肪组织，为我们提供了一个机会，探索这一领域使用反向翻译的方法。 我们建议，较高的脂肪密度（例如，较高的CT衰减）是由于炎性细胞浸润更大， 细胞，这导致更多的炎症介质的产生，并可能降低身体功能。 众所周知，脂肪库是异质的，因为它们在代谢功能上不同，以及 生化和细胞组成。基质细胞，前脂肪细胞， 和炎症细胞如脂肪中的巨噬细胞。许多证据表明，这些特定的仓库 特征可能有助于与年龄有关的健康问题;然而，病理生理机制， 不同的脂肪库影响慢性疾病和残疾还没有完全了解。尽管可以 研究人类皮下脂肪的分子和代谢特征，由于明显的原因， 可用于侵入性研究人体深层皮下、内脏、心包或肌内脂肪库。 因此，一个可靠和有效的动物模型，与相关的应用程序的变化，肥胖和相关的 健康状况与人类衰老，需要阐明生理和分子差异之间 脂肪组织库，脂肪分布随年龄变化的潜在因素，以及这些库的差异 脂肪分布的变化会导致慢性疾病和身体功能随年龄增长而下降。 这个发展项目的总体目标是纳入和扩大非人类的使用 灵长类动物资源在WFUSM的研究人类衰老，特别是研究区域脂肪组织 特征及其与衰老相关的健康状况的联系。这将通过测试特定的 假设，无论是回顾性的（使用储存的标本和生物成像扫描）和前瞻性的（使用 纵向研究），如下所述。建议的研究将改善我们的 使用这种特征良好的非人类脂肪CT衰减的生物学基础的理解 灵长类动物模型的脂肪分布和年龄相关的疾病，并将使我们能够确定的性质， 在组织学和分子水平上观察脂肪组织的组成，作为成像研究的补充。 进行脂肪组织与炎症性疾病的体外和成像评估 生物标志物和功能能力将提供必要的“概念验证”数据， 动物作为研究模型，与人类衰老相似，供OAIC研究人员将来使用。