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脂肪随衰老的重新分布与残疾有关 与年龄相关的疾病和身体机能受损的风险增加。脂肪无创成像 通过计算机断层扫描（CT）显示异常或异位位置的脂肪量，例如 内脏器官周围和肌肉内，对健康和功能产生不利影响。 除了脂肪体积之外，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（参见章节 f).然而，与骨骼肌不同，已知 CT 衰减表明甘油三酯较高 浸润，实际上对于 CT 衰减变化的性质和生物学基础一无所知 脂肪组织，为我们提供了使用反向翻译方法探索该领域的机会。 我们认为较高的脂肪密度（例如，较高的 CT 衰减）是由于炎症浸润较多 细胞，这会导致炎症介质产生更多，并可能降低身体功能。 众所周知，脂肪库是异质的，因为它们的代谢功能不同，而且 生化和细胞组成。基质细胞、前脂肪细胞、 以及脂肪中的巨噬细胞等炎症细胞。许多证据表明这些仓库特定 特征可能会导致与年龄相关的健康问题；然而，病理生理机制 哪些不同的脂肪库会影响慢性疾病和残疾，目前尚不完全清楚。虽然有可能 研究人类皮下脂肪的分子和代谢特征，由于显而易见的原因，它不是 可以侵入性地研究人体深层皮下、内脏、心包或肌肉内的脂肪库。 因此，一个可靠且有效的动物模型，与肥胖和相关的变化相关的应用 健康状况与人类衰老的关系，需要阐明之间的生理和分子差异 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的发生，并导致身体机能随着年龄的增长而下降。 该开发项目的总体目标是纳入并扩大非人类的使用 WFUSM 的灵长类资源用于人类衰老研究，特别是区域脂肪组织的研究 特征及其与衰老相关健康状况的联系。这将通过测试特定的 假设，既回顾性地（使用存储的样本和生物成像扫描）又前瞻性地（使用 纵向研究），在食蟹猴中进行，如下所述。拟议的研究将改善我们的 使用这种充分表征的非人类来了解差异脂肪 CT 衰减的生物学基础 脂肪分布和年龄相关疾病的灵长类动物模型，将使我们能够确定脂肪分布和年龄相关疾病的性质和 在组织学和分子水平上分析脂肪组织的组成，作为成像研究的补充。 对脂肪组织与炎症性疾病进行体外和成像评估 生物标志物和功能能力将为建立这一点提供必要的“概念验证”数据 动物作为与人类衰老相似的研究模型，供 OAIC 研究人员未来使用。