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. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103643-07
Application #
9504629
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of New England
Department
Type
DUNS #
071735252
City
Biddeford
State
ME
Country
United States
Zip Code
Cone, Katherine; Lanpher, Janell; Kinens, Abigail et al. (2018) Delta/mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression: assessment of therapeutic index in male Sprague Dawley rats. Psychopharmacology (Berl) 235:1609-1618
Cao, Ling; Malon, Jennifer T (2018) Anti-nociceptive Role of CXCL1 in a Murine Model of Peripheral Nerve Injury-induced Neuropathic Pain. Neuroscience 372:225-236
Gjelsvik, Kayla Jane; Follansbee, Taylor Leon; Ganter, Geoffrey Karl (2018) Bone Morphogenetic Protein Glass Bottom Boat (BMP5/6/7/8) and its receptor Wishful Thinking (BMPRII) are required for injury-induced allodynia in Drosophila. Mol Pain 14:1744806918802703
McLane, Virginia D; Kumar, Saurabh; Leeming, Reno et al. (2018) Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS. J Neuroimmunol 319:117-129
Davis, Seth M; Rice, Makaela; Rudlong, Jacob et al. (2018) Neonatal pain and stress disrupts later-life pavlovian fear conditioning and sensory function in rats: Evidence for a two-hit model. Dev Psychobiol 60:520-533
Remeniuk, Bethany; King, Tamara; Sukhtankar, Devki et al. (2018) Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain. Pain 159:684-698
Govea, Rosann M; Barbe, Mary F; Bove, Geoffrey M (2017) Group IV nociceptors develop axonal chemical sensitivity during neuritis and following treatment of the sciatic nerve with vinblastine. J Neurophysiol 118:2103-2109
Havelin, Joshua; Imbert, Ian; Sukhtankar, Devki et al. (2017) Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats. J Neurosci 37:5111-5122
Lei, Wei; Mullen, Nathan; McCarthy, Sarah et al. (2017) Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain. J Biol Chem 292:10414-10428
Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L et al. (2017) Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway. J Neurosci 37:8524-8533

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