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Targeting visceral pain through intestinal neuropod cell GUCY2C signaling

通过肠道神经足细胞 GUCY2C 信号传导治疗内脏疼痛

基本信息

批准号：
10837293
负责人：
MANUEL L COVARRUBIAS
金额：
$ 72.28万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10837293
关键词：
Abbreviations Absence of pain sensation Action Potentials Acute Affect Afferent Neurons Agonist Agreement Analgesics Anatomy Anti-Inflammatory Agents Binding Catalytic Domain Cells Cholecystokinin Chronic Clinical Colorectal Constipation Cyclic GMP Cyclic Nucleotides Data Development Diarrhea Disease Distal Elements Enterocytes Enterotoxins Etiology Extracellular Domain FDA approved Family Fire - disasters Functional disorder Genetic Guanosine Triphosphate Homologous Gene Hormone secretion Hormones Hyperalgesia Hypersensitivity In Vitro Inflammation Intestinal Secretions Intestines Irritable Bowel Syndrome Link Mediating Modeling Molecular Mus Nerve Neurons Nociception Nociceptors Non-Steroidal Anti-Inflammatory Agents Opioid Oral Outcome Pain Pain Disorder Pain management Patients Peptides Periodicity Persons Pharmaceutical Preparations Population Quality of life Receptor Activation Refractory Resistance Rodent Role Signal Transduction Small Intestines Spinal Spinal Cord Spinal Ganglia Synapses Syndrome Testing Therapeutic Translating Vertebral column Visceral Visceral Afferents Visceral pain analog colorectal distension cost disorders of gut-brain interaction dorsal horn enterotoxin receptor in vivo inhibitor insight neuronal excitability neuropsychiatric disorder neurotransmission novel novel therapeutics optogenetics overexpression pain reduction pain relief pain signal pharmacologic phosphoric diester hydrolase prevent receptor recruit repaired response selective expression side effect uroguanylin

项目摘要

Visceral hypersensitivity (VH) and pain in disorders of gut-brain interaction (DGBI), like constipation-type irritable bowel syndrome (IBS-C) or chronic idiopathic constipation (CIC), afflicts >10% of the population with reducing quality of life at a cost of ~$30B/y in the U.S. The etiology of VH in DBGI is not known. VH reflects recruitment of silent dorsal root ganglia (DRG) visceral afferents, reducing their threshold to fire, and increasing their rate of firing, action potentials. Current analgesics, including non-steroidal anti-inflammatory drugs and opiates, are inadequate, with poor efficacy and side effects, highlighting the clinical need for novel therapeutics. The intestinal receptor guanylyl cyclase C (GUCY2C) binds cognate peptides at the extracellular domain that activate an intracellular catalytic domain, converting GTP to cyclic GMP, the downstream effector. GUCY2C is the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), and the homologous hormone uroguanylin in small intestine and their receptor activation induces secretion (diarrhea for STs). This secretion is the basis for treating DBGI constipation syndromes with linaclotide (Linzess™), an ST analog, or plecanatide (Trulance™), a uroguanylin analog. Beyond secretion, GUCY2C agonists relieve pain in DBGI patients and rodents, reducing visceral nociception produced by colorectal distension (CRD). While visceral pain relief by agonists is mediated by GUCY2C, mechanisms, and their role in the pathophysiology of VH, are unknown. Interestingly, GUCY2C agonists are formulated for activity confined to small intestine. Our recent studies revealed that DBGI patients with VH lose uroguanylin, silencing GUCY2C in small intestine. Additionally, we discovered that GUCY2C is over-expressed by small intestine neuropod cells, which synapse with DRG neurons controlling gut-spinal cord signaling. Silencing GUCY2C produced spontaneous VH identical to that produced by inflammation. In close agreement, neuropod cells produce DRG neuron hyperexcitability which is eliminated by GUCY2C signaling. These data suggest a novel Anatomical Hypothesis in which neuropod cells in small intestine control the excitability of DRG neurons afferent to the spinal cord which, in turn, inhibit nociceptive signaling from CRD. The Pathophysiological Hypothesis suggests that VH in DBGI reflects uroguanylin loss, silencing GUCY2C in neuropod cells in small intestine, disrupting the control of DRG neuron excitability which amplifies colorectal nociception. The Therapeutic Hypothesis suggests that GUCY2C-cGMP signaling can be selectively amplified only in neuropod, but not other intestinal, cells to suppress neuron excitability controlling visceral pain without producing secretion and diarrhea, the major therapeutic limitation to oral GUCY2C agonists. Proposed studies will define key elements of a new gut-spinal cord axis in which GUCY2C drives neurotransmission by neuropod cells in small intestine to regulate neuron excitability controlling visceral pain in the colorectum. The potential to translate these insights into new therapeutic paradigms for VH targeting neuropod cells to maximize analgesia, but minimize diarrhea, is highlighted by the availability of oral GUCY2C agonists to treat constipation.

内脏超敏反应（VH）和疼痛在肠-脑相互作用紊乱（DGBI），如便秘型易怒