Noninvasive Measurement of UCP1 in Brown Adipose Tissue

描述(申请人提供)：我们正处于肥胖症和糖尿病的世界性流行之中。根据世界卫生组织的数据，超过10亿成年人(约占世界人口的15%)要么超重(BMI&GT；25)，要么肥胖(BMI&GT；30)，超过1.5亿成年人患有糖尿病，其中大部分是由肥胖引起的胰岛素抵抗引起的2型糖尿病。至少有两种明显可区分的脂肪：白色脂肪组织(Wat)和棕色脂肪组织(BAT)，白色脂肪组织存储能量，棕色脂肪组织燃烧能量产生热量。因此，一个人有多胖，不仅反映了S/他吃了多少，也反映了Wat对Bat可能存在的程度，以及Bat可能有多活跃。评估BAT数量和活性的方法对于评估增加BAT产热以减少肥胖的策略至关重要。我们建议设计和测试新型的RNA分子，这些分子将检测UCP1 mRNA的存在，UCP1 mRNA是BAT存在和活性的标志。这些新的RNA将是核糖开关的一部分，当生物标记物存在时，该开关激活相关的适体，该适体将结合放射性分子123I甲状腺激素，该分子可以用SPECT/CT进行定位和定量。我们将使用一种新的基于细胞的SELEX方法，研究这种核糖开关在培养的蝙蝠细胞中的传递。SPECT/CT研究将使我们能够成像和定量放射性配体对小鼠BAT组织中存在的UCP1 mRNA的摄取和保留。通过结合希伯来大学医学院PI在RNA结合领域的经验，我们的顾问/合作者在适体选择和细胞表面标记内化方面的专业知识，Joslin Pi在蝙蝠生理学和蝙蝠组织培养方面的经验，以及BIDMC Pi在核医学方面的专业知识，该项目提出了一种全新的方法，据我们所知，UCP1 mRNA是BAT存在和活性的关键标记物。

DESCRIPTION (provided by applicant): We are in the midst of worldwide epidemics of obesity and diabetes. According to the World Health Organization, over 1 billion adults (~15% of the world population) are either overweight (body mass index (BMI) >25) or obese (BMI>30) and more than 150 million adults have diabetes, most of which is type 2 diabetes driven by the insulin resistance associated with obesity. There are at least two clearly distinguishable forms of fat: white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which burns energy for thermogenesis. Thus, how "fat" an individual is not just a reflection of how much s/he eats, but also how much WAT vs. BAT might be present and how active the BAT might be. Methods for evaluating the amount and activity of BAT are crucial for evaluating strategies to increase BAT thermogenesis in order to reduce obesity. We propose to design and test novel RNA molecules that will sense the presence of UCP1 mRNA, a marker for the presence and activity of BAT. These novel RNAs will be part of a riboswitch that, when the biomarker is present, activates an associated aptamer, that will bind a radioactive molecule, 123I thyroid hormone, which can be localized and quantitated with SPECT/CT. We shall investigate delivery of this riboswitch into BAT cells in culture, using a novel cell based SELEX approach. SPECT/CT studies will enable us to image and quantitate the uptake and retention of a radioactive ligand responsive to the presence of UCP1 mRNA in BAT tissue in mice. By combining the Hebrew University Medical School PI's experience in the field of RNA binding, our consultant/collaborators' expertise in aptamer selection and internalization of cell surface markers, the Joslin PI's experience in BAT physiology and BAT tissue culture, and the BIDMC PI's expertise in nuclear medicine, this project proposes, to the best of our knowledge, a completely novel approach to specifically target and quantitate UCP1 mRNA, a key marker for the presence and activity of BAT.