Thursday, November 21, 2024
11/21/2024
Primary cilia are short hair-like structures protruding from the surface of almost all cells in the vertebrate body. In the nervous system, cilia are critical for both the development and the function of neurons, including in spinal cord, cerebral cortex, hippocampus, the nigrostriatal system, and the cerebellum. Sensory neurons of the dorsal root ganglia (DRG) elaborate a single primary cilium at their soma shortly after they are born in embryogenesis and migrate into the DRG. However, nothing is known about potential functions that primary cilia may have in the function of mature DRG neurons. Recent work in the fruit fly and in the rat have shown a role for Hedgehog signaling in nociceptive sensitization. In mammals, the Hedgehog pathway demonstrates a dependence upon primary cilia for signal transduction. This research proposal seeks to test the hypothesis that primary cilia expressed by nociceptive neurons of the DRG modulate nociceptive signals arriving from the periphery and thereby modulate nociceptive signaling under normal physiological conditions and during pathophysiological states. In Specific Aim 1 we shall investigate the importance of primary cilia in pain thresholds and in models of inflammatory and neuropathic pain in both rat and mouse models. In Specific Aim 2 we shall test the role of Hedghog signalling in the modulation of threshold, inflammatory, and chronic pain states in PIPN, and we shall examine the dependence of Hedgehog signalling upon primary cilia of DRG neurons. Aim 2 examines the hypothesis that Hedgehog signaling mediates hyperalgesia in both inflammatory and PIPN pain states. In the rat, siRNA targeting primary cilium-specific intraflagellar transport (IFT) genes will be administered to lumbar DRGs through intrathecal injection. siRNA- mediated knockdown of these genes specifically leads to a loss of the primary ciliary function. In the mouse, knock-in lines expressing a Cre recombinase integrated into the NaV1.8 locus shall be used as a tool to specifically eliminate the IFT gene Ift88 in nociceptive neurons. Pharmacological and siRNA-based modification of PIPN and Hedgehog signaling in both knockdown and wildtype rats, as well as loss-of-function and gain-of-function mouse mutants in primary cilia and in Hedgehog signaling, shall be employed. The significance of this project is that we shall elucidate Hedgehog as a new signal transduction pathway for the modification of chronic pain states, and also the locus at which it acts, the primary cilium. Both the cilium and the Hedgehog pathway offer multiple druggable targets that may prove amenable for translation into novel therapeutics for pain therapy.
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