Lysophospholipid Receptors and Signaling
Lysophospholipids, such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are small fat molecules that act through G protein-coupled receptors (GPCRs) on the surfaces of cells. We continue to study fundamental aspects of their signaling properties, and their disease roles in hydrocephalus, neuropsychiatric disorders, and neurodegenerative disorders.
Through studies of the embryonic mouse brain, we discovered the first lysophospholipid (LP) receptor (Hecht, Weiner et al. 1996), known as LPA1, which initiated the lysophospholipid receptor signaling field and enabled subsequent identification of other LP receptors for LPA, S1P, and other LPs. This class of lipid receptors now constitutes ~40% of the known lipid GPCRs. Other lab milestones included creating the first LPAR knockout mouse, which enabled the first studies of LPAR-mediated effects on the developing brain, their linkage to disease, and their binding properties. The Chun Lab continues to study fundamental aspects of lysophospholipid signaling and their roles in diseases like Multiple Sclerosis (MS), hydrocephalus, and other brain disorders. This work has contributed to the entry of four FDA-approved drugs to treat MS (fingolimod, siponimod, ozanimod and ponesimod). Ongoing studies may help lead to treatments for neurological and non-neurological disorders.
S1P and Multiple Sclerosis
S1P is one of the most studied of the lysophospholipids. It signals through five distinct GPCR subtypes: S1PR1-S1PR5. Four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) have been approved as medicines for different forms of Multiple Sclerosis, with more in clinical development. Our lab investigates the complex ligand-receptor interactions that lead to downstream signaling effects and disease modification.LPA and Hydrocephalus
Hydrocephalus is a disease of the brain where excess cerebral spinal fluid (CSF) puts pressure on the brain, altering brain morphology and resulting in cognitive, behavioral and motor impairments. Post-hemorrhagic hydrocephalus (PHH) is a complication of intraventricular brain bleeding, and most commonly occurs in neonates and premature infants. LPA is a blood-borne bioactive lipid, and its receptors are localized to the ventricular membranes. We have developed multiple models of LPA-induced PHH to examine the effects of LPA on brain morphology, behavior, cellular mechanisms, and survival.
Other Disorders and Indications
LPA and SIP signaling have been implicated in myriad disorders. Other disorders we have studied in our laboratory include neurological disorders such as neuropathic pain and schizophrenia, as well as reproduction disorders.
Interferometry
The native interactions between lysophospholipids and their receptors are difficult to measure using traditional binding assays. Compensated interferometry combined with a free-solution assay enables the quantification and analysis of binding interactions for lysophospholipid receptors in a label-free, near-native environment.