Shotgun Lipidomics Technology, Cellular Lipidome, High Throughput and Bioinformatics

Multi-dimensional mass spectrometry-based shotgun lipidomics that we have developed allows us to quantitatively analyze over 20 lipid classes, approximately 95% of the content and hundreds to thousands of lipid molecular species of a cellular lipidome directly from a lipid extract of a biological sample. However, shotgun lipidomics needs to be further developed, refined and/or extended for its penetrance into the low abundance regime of a cellular lipidome or uncovered lipid classes with high throughput and bioinformatics. Particular interests at the moment will be in the sphingolipid classes and molecular species.

Biochemical Mechanisms, Lipid Content and Metabolic Syndrome

Our recent studies by shotgun lipidomics have revealed numerous alterations in lipid content and composition including cardiolipin, acyl-CoA, acylcarnitine and triacylglycerol in numerous organs at the diabetic and/or obesity states. Accordingly, our research goal in this area is to identify the biochemical mechanism(s) underlying these altered lipid profiles and the causal roles of the altered lipid content and composition in metabolic dysfunction compromising diabetes and obesity. We will utilize a specific set of murine genetic models and the state-of-the-art shotgun lipidomics technology to address these research goals.

Biochemical Mechanisms, Sulfatide Depletion and Alzheimer's Disease

Through utilization of the enabling technology of shotgun lipidomics, we have recently revealed that a specific myelin sphingolipid, sulfatide, is substantially depleted at the very earliest clinically-recognizable stage of Alzheimer’s disease. In addition, we have uncovered that in the central nervous system: 1) sulfatides are specifically associated with apolipoprotein E (apoE)-containing high-density lipoprotein-like particles in cerebrospinal fluid; 2) apoE modulates cellular sulfatide levels; and 3) the modulation of sulfatide content is apoE-isoform dependent. Based on these findings, we have proposed a working model of sulfatide depletion in the pathogenesis of Alzheimer’s disease where Abeta peptide clearance/deposition and apoE serve as synergistic risk factors. Through exploiting the sensitivity and specificity of mass spectrometry in conjunction with novel mechanistic hypotheses and experimental designs as well as utilization of other state-of-the-art technologies (e.g., confocal fluorescence microscopy, real-time PCR, proteomics, etc.), we have generated intense interest in the roles of specialized lipids in the pathobiology of Alzheimer’s disease. In the future, we will further explore the roles of specialized lipids (e.g., sulfatide, ceramide, plasmalogen, and gangliosides) in Alzheimer’s disease as well as in other neurodegenerative diseases and neurological disorders.