Development Project 2

D.具体目标： 身体成分和脂肪分布，以及随着年龄增长脂肪的重新分布与残疾有关。 通过增加与年龄相关的疾病和身体功能受损的风险。脂肪的无创成像 计算机断层扫描(CT)显示异常或异位部位的脂肪量，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，与总肥胖度或脂肪位置无关(参见 f)。然而，与骨骼肌不同的是，CT衰减被认为是甘油三酯含量较高的标志 浸润性病变中CT衰减变化的性质和生物学基础几乎一无所知。 脂肪组织，为我们提供了一个使用反向翻译方法探索这一领域的机会。 我们认为，较高的脂肪密度(例如，较高的CT密度)是由于炎症的更大渗透所致 细胞，这会导致更多的炎症介质的产生，也许还会降低身体功能。 众所周知，脂肪库是异质性的，因为它们的代谢功能不同，而且 生化和细胞成分。基质细胞、前脂肪细胞、 脂肪中的巨噬细胞等炎性细胞。许多证据表明这些特定于仓库的 特征可能导致与年龄相关的健康问题；然而，通过 哪些不同的脂肪库会影响慢性病和残疾，目前还不完全清楚。尽管这是可能的 要研究人类皮下脂肪的分子和代谢特征，原因很明显，它不是 可侵入性地研究人类深层皮下、内脏、心包或肌肉内脂肪储存。 因此，一个可靠和有效的动物模型，相关的应用于肥胖症的变化和相关 随着人类健康状况的老化，需要阐明生理和分子上的差异 脂肪组织储存库，脂肪分布随年龄变化的潜在因素，以及这些储存库的差异 随着年龄的增长，脂肪分布的变化会导致慢性病的失效和身体机能的下降。 这个开发项目的总体目标是纳入和扩大非人类的使用 WFUSM灵长类资源用于研究人类衰老，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，既有追溯性的(使用存储的样本和生物成像扫描)，也有前瞻性的(使用 纵向研究)，在食蟹猴身上，如下所述。拟议的研究将改善我们的 利用这一具有良好特征的非人类来理解差异脂肪CT衰减的生物学基础 灵长类动物脂肪分布和年龄相关疾病的模型，并将使我们能够确定 脂肪组织在组织学和分子水平上的组成，作为成像研究的补充。 在炎症性疾病的同时进行脂肪组织的体外和影像评估 生物标志物和功能能力将为确定这一点提供必要的“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。

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.