Lysophospholipid metabolism and signalling - role of lysophospholipases

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Lysophospholipids (LysoPLs) are a class of fats (lipids) that are involved in a wide range of biological processes. LysoPLs function as critical molecular messengers that transmit cellular signals either from outside or within the cell, thus allowing for cellular communication. Recent evidence suggests that LysoPLs are required for proper cardiovascular, immune, respiratory, and reproductive system development and function, underscoring the biological importance of these lipids. However, the role of LysoPLs in cellular energy metabolism, a fundamental process that allows cells to burn energy substrates in order to support vital cell functions, remains unclear. Lysophospholipases are enzymes that break down LysoPLs and thereby modulate LysoPL levels. The overall goal of my research is to examine the role of LysoPLs in cellular energy metabolism and function and study the influence of lysophospholipases (LysoPL breakdown) on key cell communication processes. LysoPLs modulate cell communication from outside the cell by binding to specific receptors on the cell surface, which triggers molecular reactions inside the target cell. Autotaxin is a lysophospholipase that converts one type of LysoPL (lysophosphatidylcholine) into another biologically active LysoPL (lysophosphatidic acid), which has been suggested to influence energy substrate utilization. Indeed, autotaxin is present in tissues with high energy metabolism (e.g. fat tissue, liver, heart), but it remains unclear whether it is involved in regulating processes of energy metabolism. One aim of my research is to explore the role of autotaxin in the regulation of energy metabolism in mammalian cells. Although most LysoPL-mediated cell communication processes known to date are initiated by LysoPLs from outside the cell, LysoPLs are also gaining recognition as molecular messengers that operate from within the cell. Thus, LysoPL breakdown inside the cell is also likely to regulate important communication processes. We have previously identified a novel lysophospholipase (neuropathy target esterase-related esterase (NRE)), which degrades a specific type of LysoPLs. Our prior results suggest that this lysophospholipase could be involved in cellular energy metabolism. A major focus of this research will be the exploration of the role of NRE in intracellular LysoPL breakdown and signalling as well as the study of its involvement in cellular energy substrate utilization. Another goal of my research program is to search for previously unrecognized lysophospholipases and study their importance in regulating cellular communication, energy metabolism and function. To date, only a few lysophospholipases have been identified and their biological roles are incompletely understood. Characterizing the roles of identified and novel lysophospholipases will provide the basis for a comprehensive long-term LysoPL research program. Findings obtained with the proposed research will advance our understanding of the biological role of LysoPL messengers and how these biologically active lipids control cellular energy metabolism. Thus, this research will make important contributions to the field of lipid, cell communication (signalling), and energy metabolism research. The proposed research program will increase the global visibility of LysoPL research in Canada and expand opportunities for collaboration. Importantly, this program will provide a cutting-edge training environment for the next generation of highly qualified personnel. I will train students and research personnel to become leading scientists of tomorrow and equip them with skill sets that allow them to pursue successful careers in academia or industry.