PROJECT ABSTRACT Obesity leads to an increased risk for type 2 diabetes, heart attack, hypertension, stroke, and many types of cancer—conditions which are among the leading causes of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The long-term objective of our studies is to determine how genetic variation predisposes humans to obesity and the accompanying therapeutic implications. Here we are optimizing the development of a state-of-the-art approach based on CRISPR-mediated gene downregulation in a temporally, anatomically and cell-type specific manner, to rapidly test whether genes in which variation predisposes to obesity are required for the function of specialized neurons in the mouse hypothalamus. We will also be using this approach to test the hypothesis that genes in which mutations cause obesity by affecting the function of the primary cilia, a cell surface projection that receives and transduces select intercellular signals, are required for the function of neurons of central leptin-melanocortin system in mice.