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.
Brown fat tissue (BAT), unlike the usual white fat, when activated, can burn calories, and thus contribute to weight loss. We propose an entirely new approach to the in vivo localization and quantitation of UCP1, a key marker for brown adipose tissue (BAT). We intend to use small RNA molecules that recognize molecules located inside BAT cells, which are specific for BAT (UCP1). When these RNA molecules bind to UCP1 specific mRNA it causes the opening of a binding site for another, radioactive, molecule, T3 that is administered intravenously. The radioactivity can then be detected and quantitated with the standard nuclear medicine technique, SPECT/CT. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers'commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.
|Ussar, Siegfried; Lee, Kevin Y; Dankel, Simon N et al. (2014) ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med 6:247ra103|
|Lee, Kevin Y; Kahn, C Ronald (2012) Turning on brown fat and muscle metabolism: hedging your bets. Cell 151:248-50|