Endogenous optical biomarkers of adipose tissue function

 描述(申请人提供)：超过30%的美国人患有肥胖症，每年造成近1470亿美元的医疗和经济负担。有效的反肥胖干预措施的发展可能导致肥胖症和人类健康相关方面的显著改善。脂肪组织(AT)有三种不同的类型。白色(Wat)仓库用于储能，而棕色(BAT)和米色(BAT)仓库消耗能量产生热量。因此，导致BEAT/BAT激活患病率增加的方法已成为有希望的抗肥胖干预措施。WAT和BAT具有不同的表型和基因组特征，BAT通常由更广泛的血管网络和具有更小的脂滴、致密和更突出的线粒体网络的细胞组成。BEAT在表型和功能上与BAT相似，但主要在WAT仓库中发现。非侵入性成像方法，如PET和漫反射光学成像，已被用于检测整个动物和人类的BAT/BEAT，但缺乏分辨率和对AT型的特异性；传统的检测方法是侵入性的。因此，总体目标是 这个项目的重点是开发最小侵入性的，因此，潜在地可重复的高分辨率 光学成像方法识别BAT、WAT和BEAT，从而使高效开发减肥治疗成为可能。这项建议的具体目标是识别和验证不同AT及其功能状态的高分辨率内源性荧光和散射定量生物标志物。我们建议在APN动物模型中评估线粒体的光学氧化还原比率和组织、脂滴的生化和形态特征以及血管形成作为AT型(AIM 1)的生物标志物。我们将使用免疫组织化学和基因和蛋白质表达分析来验证这些光学生物标记物，我们将证明它们可以用于在细胞水平上监测旨在诱导BAT/BEAT激活的热源处理的效果(目标2)。这些研究的预期结果是一套新的AT类型和功能状态的光学生物标记物，可用作开发有效的抗肥胖干预措施的有力辅助。

 DESCRIPTION (provided by applicant): Over 30% of Americans are obese, creating a medical and economic burden approaching $147 billion annually. The development of effective anti-obesity interventions could lead to significant improvements in obesity and related aspects of human health. Three distinct adipose tissue (AT) types have been identified. White (WAT) depots are used for energy storage, while brown (BAT) and beige (BeAT) depots consume energy to produce heat. Therefore, approaches that lead to enhanced prevalence of activation of BeAT/BAT have emerged as promising anti-obesity interventions. WAT and BAT have distinct phenotypes and genomic identities, with BAT typically consisting of a more extensive vascular network and cells that have smaller lipid droplets, dense and more prominent mitochondrial networks. BeAT is phenotypically and functionally similar to BAT, but is found among predominantly WAT depots. Non-invasive imaging methods, such as PET and diffuse optical imaging, have been used to detect BAT/BeAT in whole animals and humans, but lack in resolution and specificity to AT type; traditional assays are invasive. Thus, the overall objective of this project is to develop minimally invasive, and thus, potentially repeatable, high-resolution optical imaging methods to identify BAT, WAT and BeAT, in order to enable efficient development of anti-obesity treatments. The specific objective of this proposal is the identification and validation of high-resolution endogenous fluorescence and scattering-based quantitative biomarkers of different ATs and their functional state. We propose to assess mitochondrial optical redox ratio and organization, lipid droplet biochemical and morphological characteristics, and vascularization as biomarkers of AT type (Aim 1) in apn animal model that exhibits increased BeAT depots. We will employ immunohistochemical and gene and protein expression assays to validate these optical biomarkers, and we will demonstrate that they can be used to monitor at the cellular level the effects of thermogenic treatment designed to induce BAT/BeAT activation (Aim 2). The expected outcome of these studies is a set of novel optical biomarkers of AT type and functional state that can be used as a powerful aid in the development of effective anti-obesity interventions.