A5003634687- Sphingolipid Metabolism and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Neonatal and fetal brain pathology
- Alzheimer's disease research and treatments
- Endoplasmic Reticulum Stress and Disease
- GDF15 and Related Biomarkers
- Neurogenesis and neuroplasticity mechanisms
- Nuclear Receptors and Signaling
- Regulation of Appetite and Obesity
- Multiple Sclerosis Research Studies
- Lipid Membrane Structure and Behavior
- Adipose Tissue and Metabolism
- Lysosomal Storage Disorders Research
- Anesthesia and Neurotoxicity Research
- Telomeres, Telomerase, and Senescence
- Sleep and Wakefulness Research
- Alcoholism and Thiamine Deficiency
- Neurobiology and Insect Physiology Research
- Neuropeptides and Animal Physiology
- Lipid metabolism and biosynthesis
- Cytokine Signaling Pathways and Interactions
- Amyotrophic Lateral Sclerosis Research
- Traumatic Brain Injury and Neurovascular Disturbances
- Inflammasome and immune disorders
- Fibroblast Growth Factor Research
The University of Sydney
2018-2024
Cooperative Trials Group for Neuro-Oncology
2023-2024
UNSW Sydney
2015-2022
Centenary Institute
2018-2021
Insulin signaling in the brain has been implicated control of satiety, glucose homeostasis and energy balance. However, insulin is dispensable controlling AgRP or POMC neurons it unclear which other regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs across phyla.
Abstract Specific forms of the lipid ceramide, synthesized by ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 as a driver insulin resistance in liver and adipose tissue. C18 1 (CerS1), is abundant skeletal muscle suggested promote humans. We herein describe first isoform-specific inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 highly selective for CerS1. Daily...
Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions C9orf72 are two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration FTD (FTD-GRN) or (FTD-C9orf72) abnormalities unknown, although evidence from mouse cell culture models suggests that disrupt lysosomal lipid catabolism. To determine how brain metabolism is affected familial inclusions, this related to myelin markers, we undertook...
Abstract Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding biochemical changes that sensitize ageing brain to neurodegeneration will provide new opportunities prevention treatment. This study aimed determine how major genetic factors affect hippocampal proteome lipidome neurologically-normal humans over age 65. hippocampus was chosen as it is highly susceptible atrophy with in several neurodegenerative diseases. Methods...
Abstract Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause cancer-associated death worldwide. With increasing prevalence metabolic conditions, non-alcoholic fatty disease (NAFLD) is emerging as fastest-growing HCC risk factor, and it imposes an additional layer difficulty in management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating development NAFLD-associated HCC. However, exactly which...
Abstract Sphingosine 1‐phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein‐coupled receptors, S1PR1‐S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) potent S1P receptor agonist causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties FTY720 in several neurodegenerative paradigms; however, the native ligand have not been established. We aimed establish significance...
Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P SK2 activity early Alzheimer's disease (AD) pathogenesis, an inverse correlation between hippocampal levels age females, leading us to speculate that sensitizing influence for AD. Paradoxically, was mediate amyloid β (Aβ) formation from precursor protein (APP) vitro . To determine whether...
The number, position, and configuration of double bonds in lipids affect membrane fluidity the recruitment signaling proteins. Studies on mammalian sphingolipids have focused those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), we observed marked accumulation containing di-unsaturated sphingadiene base hippocampus mice lacking metabolic enzyme kinase 2 (SphK2). were localized to...
Abstract The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability function. GalCer ST synthesized mostly from C22‐C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement sphingolipid synthesis in biosynthesis stability, we mice lacking CerS2 specifically myelinating cells (CerS2 ΔO/ΔO ). At 6 weeks of age, normal‐appearing had formed mice, however there was a reduction thickness percentage myelinated...
Abstract Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1‐phosphate (S1P) is an essential lipid metabolite signals through five G‐protein coupled receptors. S1P receptor agonists such as Fingolimod valuable immunosuppressants used treat multiple sclerosis, survival. However, the role for endogenous S1P, synthesized by enzyme sphingosine kinase 2 (SphK2), myelination has not been...
Abstract Cellular senescence leads to the functional decline of regenerative cells such as mesenchymal stromal/stem (MSCs), which gives rise chronic conditions and contributes poor cell therapy outcomes. Aging tissues are associated with extracellular matrix (ECM) dysregulation, including loss elastin. However, role ECM in modulating is underexplored. In this work, it shown that tropoelastin, soluble elastin precursor, not only a marker young MSCs but also actively preserves fitness delays...
Insulin is known to act in the central nervous system regulate several physiological and behavioural outcomes, including energy balance, glucose homeostasis cognitive functioning. However, neuronal populations through which insulin enhances performance remain unidentified. receptors are found neuropeptide-Y (NPY) expressing neurons, abundant hypothalamus hippocampus; regions involved feeding behaviour spatial memory, respectively. Here we show that mice with a tissue specific knockout of NPY...
Abstract The number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, recruitment signalling proteins. Studies on mammalian sphingolipids have focused those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids diunsaturated sphingadiene base been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation lipids containing base, not...
Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases such as multiple sclerosis. Sphingosine 1-phosphate (S1P) receptor agonists Fingolimod, Siponimod, Ozanimod, Ponesimod, others clinical immunosuppressants used treat Clinical evidence suggests these drugs also have direct neuroprotective actions the CNS, however experimental support this hypothesis is lacking. S1P an essential lipid metabolite signals...
Abstract The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability function. GalCer ST synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement sphingolipid synthesis in lipid biosynthesis stability, we mice lacking CerS2 specifically myelinating cells (CerS2 ΔO/ΔO ). At 6 weeks of age, normal-appearing had formed mice, however there was a reduction thickness percentage...
Abstract Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod valuable immunosuppressants used treat multiple sclerosis, survival. However, the role for endogenous S1P, synthesized by enzyme sphingosine kinase 2 (SphK2), myelination has not been...