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Endoplasmic Reticulum Stress Responses in Pain

疼痛中的内质网应激反应

基本信息

批准号：
10579846
负责人：
Mario Danilo Boada
金额：
$ 39.63万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579846
关键词：
Acceleration Acetic Acids Acute Pain Address Affect Behavior Behavioral Bioinformatics Biological Assay Biology Cells Cluster Analysis Communities Development Dinoprostone Electrophysiology (science)Endoplasmic Reticulum Exhibits Foundations Gene Expression Genes Genetic Transcription Human Hypersensitivity Immune Immunology In Situ Incidence Individual Inflammation Inflammatory Injury Knockout Mice Label Leucocytic infiltrate Leukocytes Ligation Medical Modeling Molecular Mus Nanotechnology Nerve Degeneration Neuroimmune Neurons Nociceptors Operative Surgical Procedures Outcome Pain Patients Pattern Pattern recognition receptor Peripheral Peripheral nerve injury Persistent pain Phenotype Phosphotransferases Physical assessment Positioning Attribute Preventive Process Production Prostaglandins Protein Biosynthesis Proteins Quality of life Recovery Recovery of Function Regulation Resolution Role Signal Transduction Social Impacts Surgical incisions Technology Testing Therapeutic Tissues Toll-like receptors XBP1 gene arm biological adaptation to stress chronic inflammatory disease chronic neuropathic pain chronic pain chronic pain management clinically relevant conditional knockout cytokine economic impact effective therapy endoplasmic reticulum stress gain of function genetic signature genome-wide immune activation immune cell infiltrate improved in vivo inflammatory pain inhibitor injured innovation loss of function misfolded protein mouse model nerve injury neurobiotin novel painful neuropathy partial recovery pharmacologic prevent programs recruit response sciatic nerve single-cell RNA sequencing small molecule tool transcriptomics

项目摘要

Summary Peripheral nerve injury activates pattern recognition receptors (i.e. Toll-like receptors) in immune cells, thus triggering and maintaining inflammation, and ultimately determining the perpetuation of pain. Immune cell activation demands high levels of protein synthesis, folding and secretion, which are regulated by the endoplasmic reticulum (ER). An excessive demand in protein handling can evoke ER stress (accumulation of misfolded proteins) and consequently trigger robust activation of the unfolded protein response (UPR). IRE1α- XBP1 is the most evolutionarily conserved arm of the UPR and can be directly activated via Toll-like receptor engagement to promote the expression of pro-inflammatory factors. We have unveiled that conditional knockout (cKO) mice devoid of IRE1α/XBP1 in immune cells (Ern1/Xbp1f/f-Vav1cre), display decreased PGE2 production in vivo, reduced nociceptor responsiveness, and faster resolution of non-reflexive pain-related behaviors following paw incision. Similarly, these cKO mice exhibit improved recovery after partial sciatic nerve ligation (PSNL). Through unbiased genome-wide transcriptomic analyses we found that IRE1α-XBP1 signaling in leukocytes is critically required for the induction of prostanoids, cytokines and other novel factors such as Nupr1 (associated with chronic inflammatory diseases in humans). Of note, IRE1α-XBP1 overactivation has been correlated with painful or inflammatory conditions in humans. Therefore, we hypothesize that IRE1α-XBP1 signaling in leukocytes governs peripheral neuro-immune interactions and the development of chronic pain. Using cutting-edge experimental approaches, we will accomplish the following specific aims: 1) Determine how IRE1α-XBP1 signaling dictates the dynamics of immune cell infiltration and molecular changes that drive behavioral non-reflexive hypersensitivity following peripheral nerve injury. We postulate that the IRE1α-XBP1 arm operates as a key modulator of pro-algesic factors in immune cells, and that Nupr1 is a novel XBP1- dependent factor (using ChIP PCR) implicated in PSNL. 2) Establish how IRE1α-XBP1 activation governs individualized immune cellular reprogramming and how this drives the cross-talk with nociceptor afferents following peripheral nerve injury. Our hypothesis is that the reduced hypersensitivity observed in our cKO mice following PSNL is determined by discrete gene signatures in specific injury-infiltrating leukocyte subsets (using single cell RNA sequencing), and by the acquisition of a less responsive phenotype in nociceptors (via in vivo intracellular DRG recordings). 3) Define the therapeutic potential of inhibiting IRE1a to accelerate recovery from PSNL. We posit that pharmacological inhibition of IRE1α using MKC8866 (RNAase domain inhibitor) or KIRA6 (kinase domain inhibitor) will prevent or treat chronic neuropathic pain. Our team has expertise in pain biology and neuroimmune interactions (Romero-Sandoval), immunology and ER stress biology (Cubillos-Ruiz), in vivo electrophysiology (Boada), and scRNAseq and bioinformatics (Miller). Thus, we are uniquely positioned to test our innovative hypothesis and contribute to the development of novel non-narcotic treatments for chronic pain.

总结