Disturbances in lipid metabolism are at the core of several major health issues facing modern society, including cardiovascular disease (CVD), obesity, and type 2 diabetes (T2D). CVD is the leading cause of death from non-communicable diseases in Qatar and the incidence of heart attacks as well as strokes among young Qataris is one of the highest in the world. According to the Qatar Biobank (QBB), the prevalence of obesity and T2D in Qatar is very high, with an estimated 40% and 20% of the population being obese and/or diabetic, respectively. Thus, Qatar is facing a cardiometabolic health crisis, with wide-ranging health, social and economic consequences. The current proposal aims to explore and validate new therapeutic targets using human cell models relevant to cardiometabolic disease. These model systems will be generated from human stem cells in collaboration with a team at QBRI.

The team recently completed several molecular screens, including yeast-two-hybrid and siRNA/shRNA screens, to identify novel regulators of lipid metabolism. For example, they have performed siRNA screens targeting protein kinases, protein phosphatases, and factors involved in protein degradation. The purpose of the current work is to validate the most interesting genes and proteins identified in these screens and determine how they control lipid metabolism. In order to complete this, the corresponding genes will either be overexpressed or inactivated in the human cell models described above. The team will also use CRISPR/Cas9 gene editing to establish knock-out cell models for the most promising hits in the screens. Taken together, these experiments will form the basis for the team’s efforts to determine if any of the genes/proteins identified in the screens could be considered as potential drug targets.