Role of Nociceptor Primary Cilia in Inflammatory and Neuropathic Pain

伤害感受器初级纤毛在炎症和神经性疼痛中的作用

• 批准号: 10575524
• 负责人: KERRY L TUCKER
• 金额: $ 39.05万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575524
• 关键词: Acute; Address; Adult; Afferent Neurons; Animals; Axon; Binding; Brain; Carrier Proteins; Cell surface; Cells; Cerebellum; Cerebral cortex; Cilia; Complex; Corpus striatum structure; Cre driver; Data; Dependence; Development; Drosophila genus; Electrophysiology (science); Embryonic Development; Enterobacteria phage P1 Cre recombinase; Erinaceidae; Family; Genes; Genetic Transcription; Hair; Hippocampal Formation; Hippocampus (Brain); Hyperalgesia; Inflammatory; Intrathecal Injections; Knock-in; Ligands; Mammals; Mediating; Modeling; Modification; Mus; Mutant Strains Mice; Nervous system structure; Neurons; Nociception; Nociceptors; Organelles; Pain; Pain Threshold; Pain management; Pathway interactions; Pharmacology; Physiological; Play; Process; Proteins; Rattus; Research; Research Proposals; Rodent Model; Role; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Structure; Substantia nigra structure; Surface; System; Testing; Translations; Work; anterograde transport; base; body system; chronic pain; conditional knockout; druggable target; gain of function; hedgehog signal transduction; inflammatory pain; information processing; innovation; knock-down; loss of function; mouse model; mutant; neuronal cell body; nigrostriatal system; novel therapeutics; pain signal; painful neuropathy; receptor; response; retrograde transport; smoothened signaling pathway; tool

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.

初级纤毛是毛发状的短结构，从几乎所有细胞的表面突出