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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）和肠-脑相互作用障碍（DGBI）中的疼痛，如便秘型易激惹肠综合征（IBS-C）或慢性特发性便秘（CIC），折磨>10%的人群，在美国，以约300亿美元/年的成本改善生活质量。DBGI中VH的病因尚不清楚。VH反映征聘情况沉默的背根神经节（DRG）内脏传入，降低其阈值火，并增加其速率放电动作电位目前的镇痛药，包括非甾体抗炎药和阿片类药物，然而，目前的治疗方法不足，疗效差，副作用大，突出了对新疗法的临床需求。肠受体鸟苷酸环化酶C（GUCY 2C）在细胞外结构域结合同源肽，胞内催化结构域，将GTP转化为环GMP，下游效应物。GUCY 2C是受体对于大肠杆菌热稳定肠毒素（ST），以及小细胞中的同源激素尿鸟苷素，肠及其受体激活诱导分泌（ST腹泻）。这种分泌物是治疗的基础使用利那洛肽（Linzess™）（一种ST类似物）或普尼卡地平（Trulance™）（一种ST类似物）的DBGI便秘综合征尿鸟苷素类似物。除了分泌外，GUCY 2C激动剂还可缓解DBGI患者和啮齿动物的疼痛，由结肠直肠扩张（CRD）产生的内脏伤害性感受。虽然通过激动剂介导的内脏疼痛缓解通过GUCY 2C，机制和它们在VH的病理生理学中的作用是未知的。有趣的是，GUCY 2C 激动剂被配制成具有局限于小肠的活性。我们最近的研究表明，DBGI患者 VH失去尿鸟苷素，在小肠中沉默GUCY 2C。此外，我们发现GUCY 2C是由小肠神经足细胞过度表达，其与控制肠脊髓的DRG神经元突触塞绳信令沉默GUCY 2C产生的自发性VH与炎症产生的VH相同。在与此相似，神经足细胞产生DRG神经元过度兴奋，其被GUCY 2C消除发信号。这些数据提出了一个新的解剖学假说，即小肠中的神经足细胞控制着传入脊髓的DRG神经元的兴奋性，其反过来抑制来自CRD的伤害性信号传导。病理生理学假说表明，DBGI中的VH反映了尿鸟苷素的丢失，使GUCY 2C沉默在小肠的神经足细胞中，破坏了DRG神经元兴奋性的控制，伤害感受治疗假说表明，GUCY 2C-cGMP信号可以被选择性放大，只有在神经足细胞中，而不是其他肠细胞，抑制控制内脏疼痛的神经元兴奋性，产生分泌和腹泻，这是口服GUCY 2C激动剂的主要治疗限制。拟定研究将定义新的肠-脊髓轴的关键要素，其中GUCY 2C通过神经足驱动神经传递小肠中的神经细胞，以调节控制结肠直肠内脏疼痛的神经元兴奋性。的潜力将这些见解转化为VH靶向神经足细胞的新治疗范例，以最大化镇痛，但使腹泻最小化的优点通过口服GUCY 2C激动剂治疗便秘的可用性而突出。