Lysophospholipid metabolism and signalling - role of lysophospholipases

溶血磷脂（LysoPL）是一类参与广泛生物过程的脂肪（脂质）。LysoPL作为关键的分子信使，从细胞外或细胞内传递细胞信号，从而允许细胞通讯。最近的证据表明，LysoPL是适当的心血管，免疫，呼吸和生殖系统发育和功能所必需的，强调了这些脂质的生物学重要性。然而，LysoPLs在细胞能量代谢中的作用，这是一个允许细胞燃烧能量底物以支持重要细胞功能的基本过程，仍然不清楚。溶血磷脂酶是分解LysoPL并由此调节LysoPL水平的酶。我研究的总体目标是研究LysoPL在细胞能量代谢和功能中的作用，并研究溶血磷脂酶（LysoPL分解）对关键细胞通讯过程的影响。LysoPL通过与细胞表面上的特异性受体结合，从而触发靶细胞内的分子反应，从细胞外调节细胞通讯。自分泌运动因子是一种溶血磷脂酶，它将一种类型的溶血磷脂酰胆碱（LysoPL）转化为另一种生物活性溶血磷脂酸（LysoPL），这被认为会影响能量底物的利用。实际上，自分泌运动因子存在于具有高能量代谢的组织（例如脂肪组织、肝脏、心脏）中，但其是否参与调节能量代谢过程仍不清楚。本研究的目的之一是探讨autotaxin在哺乳动物细胞能量代谢调节中的作用。尽管迄今为止已知的大多数LysoPL介导的细胞通讯过程是由细胞外的LysoPL启动的，但LysoPL也被认为是细胞内的分子信使。因此，细胞内LysoPL的分解也可能调节重要的通讯过程。我们以前已经确定了一种新的溶血磷脂酶（神经病变靶向酯酶相关酯酶（NRE）），降解特定类型的LysoPL。我们先前的研究结果表明，这种溶血磷脂酶可能参与细胞的能量代谢。本研究的一个主要重点将是探索NRE在细胞内LysoPL分解和信号传导中的作用，以及研究其参与细胞能量底物利用。我的研究计划的另一个目标是寻找以前未被识别的溶血磷脂酶，并研究它们在调节细胞通讯，能量代谢和功能中的重要性。迄今为止，只有少数溶血磷脂酶已被确定，其生物学作用不完全了解。鉴定和新的溶血磷脂酶的作用的特点将提供一个全面的长期LysoPL研究计划的基础。这项研究的结果将促进我们对LysoPL信使的生物学作用以及这些生物活性脂质如何控制细胞能量代谢的理解。因此，这项研究将为脂质，细胞通讯（信号）和能量代谢研究领域做出重要贡献。拟议的研究计划将提高加拿大LysoPL研究的全球知名度，并扩大合作机会。重要的是，该计划将为下一代高素质人才提供先进的培训环境。我将培养学生和研究人员成为未来的领先科学家，并为他们提供技能，使他们能够在学术界或工业界追求成功的职业生涯。

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.