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.

内脏过敏 (VH) 和肠脑相互作用障碍 (DGBI) 引起的疼痛，例如便秘型烦躁肠道综合征 (IBS-C) 或慢性特发性便秘 (CIC) 困扰着 >10% 的人口，其症状减少在美国，生活质量的成本约为 30B/y。 DBGI 中 VH 的病因尚不清楚，该病因反映了招募。沉默背根神经节（DRG）内脏传入，降低其发射阈值，并增加其发射率目前的镇痛药，包括非甾体类抗炎药和阿片类药物。不足，疗效差且副作用大，凸显了临床对新疗法的需求。受体鸟苷酸环化酶 C (GUCY2C) 与胞外域的同源肽结合，激活胞内催化结构域，将 GTP 转化为环 GMP，下游效应器为 GUCY2C 受体。用于引起腹泻的细菌热稳定性肠毒素 (ST)，以及小肠中的同源激素尿鸟苷素肠道及其受体激活会诱导分泌（ST 腹泻）。这种分泌是治疗的基础。 DBGI 便秘综合征，使用 ST 类似物利那洛肽 (Linzess™) 或普卡那肽 (Trulance™) 除了分泌外，GUCY2C 激动剂还可以缓解 DBGI 患者和啮齿动物的疼痛，从而减轻疼痛。结直肠扩张 (CRD) 产生内脏伤害性感受，而激动剂则可缓解内脏疼痛。 GUCY2C 的机制及其在 VH 病理生理学中的作用尚不清楚。我们最近的研究表明，激动剂的活性仅限于小肠。随着VH失去尿鸟苷蛋白，小肠中的GUCY2C被沉默。此外，我们发现GUCY2C是小肠神经足细胞过度表达，这些细胞与控制肠道脊髓的 DRG 神经元突触沉默 GUCY2C 产生的自发 VH 与炎症产生的 VH 相同。非常一致，神经足细胞产生 DRG 神经元过度兴奋，该兴奋被 GUCY2C 消除这些数据提出了一种新的解剖学假说，其中小肠中的神经足细胞控制。传入脊髓的 DRG 神经元的兴奋性，进而抑制 CRD 的伤害性信号传导。病理生理学假说表明 DBGI 中的 VH 反映了尿鸟苷蛋白丢失，沉默了 GUCY2C 在小肠的神经足细胞中，破坏 DRG 神经元兴奋性的控制，从而放大结直肠治疗假说表明 GUCY2C-cGMP 信号传导可以被选择性放大。仅在神经足细胞中，但不在其他肠道细胞中抑制神经元兴奋性，控制内脏疼痛，而无需产生分泌物和腹泻，这是口服 GUCY2C 激动剂的主要治疗限制。将定义新肠-脊髓轴的关键要素，其中 GUCY2C 通过 Neuropod 驱动神经传递小肠细胞调节神经元兴奋性，控制结直肠内脏疼痛。将这些见解转化为针对神经足细胞的 VH 的新治疗范例，以最大限度地发挥镇痛作用，但口服 GUCY2C 激动剂可用于治疗便秘，从而最大限度地减少腹泻。