Project Details
Projekt
Physiological interaction of oxidized phospholipids, apolipoprotein A1, ABC transporter activity and cholesterol homeostasis in neuropathy and its resolution
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
In this project, we aim to investigate whether and how ABC transporter activity and apolipoproteins are contributing to natural mechanisms of pain resolution. Recently, we have introduced oxidized phospholipids (OxPL) as new targets to treat inflammatory pain. On a molecular, cellular and behavioral level, we uncovered new mechanisms of pain control by targeting the algesic function of OxPL with D-4F. D-4F is a structural mimetic of apolipoprotein A1 (ApoA1). ApoA1, in turn, is essential for formation of high density lipoproteins (HDL) and the metabolism of triglycerides, cholesterol and phospholipids. ApoA1 and HDL show anti-atherogenic and anti-inflammatory properties. The ApoA1-mimetic peptide D-4F can act as a scavenger that acutely binds OxPL, but can also stimulate the ATP-binding cassette (ABC) transporter ABCA1, an active transporter regulating cholesterol homeostasis. Here, we hypothesize that regulated activation of the endogenous ABCA1/ApoA1/HDL axis as well as local scavenging of oxidized phospholipids are part of natural mechanisms of pain resolution. In our working program, we will use cultured DRG neurons, calcium imaging and patch clamp recording in order to find out whether and how ApoA1, HDL, and ABC transporters contribute to nociceptor excitation. Lentiviral vectors will be used in gain- and loss-of-function experiments to genetically interfere with the ABC-transporter/ApoA1 system. In the model of chronic constriction injury of the sciatic nerve, we aim to use immunohistochemistry, advanced microscopy and qPCR to investigate molecular-cellular changes in the nerve and in the DRG. We want to answer how key components in the apolipoprotein-ABC transporter system change during development and resolution of neuropathic pain. As our data point to ABCA1 in the center of ApoA1/HDL function, we plan to develop inducible, cell-type specific ABCA1 knockout mice for hypothesis validation. In a translational approach, we ask whether there is an association between pain resolution phenotypes and HDL-Cholesterol and apolipoprotein concentration in the serum of patients. We expect to understand on a molecular-cellular level, how apolipoproteins and ABC transporter activity interact to balance nociceptor excitability and pain behavior. Our results may be of translational relevance for new strategies to support or induce pain resolution in transient and chronic neuropathic pain.
DFG Programme
Clinical Research Units
