University of Pittsburgh

Every single one of our 40 trillion cells must execute an intricate yet precise molecular choreography at its surface membrane. In this way cells synchronize the uptake of nutrients, processing of signals, building of tissues and even triggering the cells’ own demise. Viewed from such a perspective, most diseases that affect the human body are intriguing because they influence only some of these processes, leaving most unperturbed. Consider a cancer cell; it grows uncontrollably and refuses to die due to aberrant signaling mechanisms, yet maintains the capacity to move and nourish itself. Our lab studies a vital family of lipid molecules, the inositol lipids, that normally regulate and coordinate these essential membrane processes. We uncover fundamental new mechanisms that explain how these molecules choreograph membrane function, and – crucially – why some lipid-dependent functions fail in disease, while others are spared. To do this, we develop novel probes and tools using genetic engineering to probe living cell membranes in real time under the microscope. Some current projects include:

• Mapping the molecular organization of the membrane during normal physiology, and how this changes during oncogenic signaling. We use cutting-edge super-resolution and single molecule imaging approaches to accomplish this. We aim to identify the composition of specific molecular complexes that might be targetable with drugs to disrupt oncogenic signaling.
• Working out the detailed control mechanisms for lipid signaling in smooth muscle cells, and how this is altered during diseases like hypertension and asthma. A combination of chemical and molecular genetics is used here, along with traditional biochemical and novel single-cell assays. We aim to identify new drug targets to control smooth muscle cell contraction in these diseases.
• Identifying how aberrant accumulation of signaling lipids leads to targeted disruption of cellular function, and what mechanisms could be brought into play to correct this. The aim is to apply this knowledge to genetic diseases that cause aberrant lipid accumulation, leading to diseases as diverse as neurodegeneration and polycystic kidney disease. We apply a range of state-ofthe- art gene editing and novel chemical genetic tools to study this problem at the single cell level.