Genetic control of nociceptor anatomical plasticity in the adult peripheral nervous system

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Many human clinical conditions are associated with misrelated loss or growth of sensory axons in peripheral tissue. These conditions are often associated with chronic/persistent pain. Examples are many and diverse, ranging from the painful progressive innervation loss experienced by many diabetic patients, to hyperdense nociceptor innervation associated with pelvic pain, to neuropathic pain following tissue and nerve injuries. In spite of a clear association between intractable chronic pain, nociceptor sensitization and innervation density, there are currently no pharmaceutical treatments designed to modify the extent of sensory fibers – either to promote re-growth or to control overgrowth. It is hoped that by elucidating the molecular control of axon growth processes, we may be able develop therapies to re-establish innervation homeostasis required to alleviate pain. Sensory neurons have a limited but significant capacity to grow following peripheral injury. We determined that nociceptors grow by 2 distinct modes: 1) regeneration after direct injury to their axons - termed injury-regeneration (IR) and 2) growth of near- by uninjured nociceptors, which extend collaterals to re-establish lost innervation - termed uninjured-sprouting (US). Using transcriptomic technology, we discovered striking differences in 3’ Untranslated Region (3’-UTR) transcript isoforms between these 2 modes of growth. These distinct patterns of 3’-UTR expression are predicted to promote physical interaction with different RNA-binding proteins (RBPs). We theorize that US and IR are distinct modes of axon outgrowth differentiated by the interplay between contrasting groups of 3’UTR isoforms and the different RBPs that regulate these transcripts. Our long term goal is to develop therapeutics that target growth mode-specific RBPs to modify distinct forms of nociceptor morphogenesis that are dysregulated under pathological conditions that lead to chronic pain. To work towards this goal, in this proposal we will determine the role of RNA-binding proteins (RBPs) in 3’UTR isoform regulation during distinct modes of axon outgrowth: Injury-Regeneration (IR) and Uninjured-Sprouting (US). Studies will fall into 3 aims. In aim 1 we will determine the role of RBPs during US and in aim 2 we will determine the role of RBPs during IR. The third aim will examine the role of 3’UTR isoform expression in neuropathic pain after sciatic nerve crush injury. This proposal tests a highly novel mechanism for the regulation of nociceptive fiber growth. The proposed experiments will elucidate molecular mechanisms underlying distinct modes of axonal outgrowth (IR and US) that may contribute to development of neuropathic pain. !