The Role of the Voltage-Gated Sodium Channel, NaV1.8, in Silent Inflammatory Bowel Disease

电压门控钠通道 NaV1.8 在无症状炎症性肠病中的作用

• 批准号: 9981094
• 负责人: MATTHEW D COATES
• 金额: $ 34.87万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981094
• 关键词: Abdominal Pain; Abscess; Action Potentials; Affect; Afferent Neurons; Animal Model; Biological Markers; Biophysics; Cells; Characteristics; Clinical Treatment; Congenital Pain Insensitivity; Crohn' s disease; Defect; Development; Diagnostic; Disease; Disease Management; Electrophysiology (science); Esthesia; Excision; Exhibits; Fistula; Frequencies; Functional disorder; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic Polymorphism; Genotype; Healthcare; Homozygote; Human; Impairment; Individual; Inflammation; Inflammatory Bowel Diseases; Intestines; Label; Lead; Link; Mediating; Methods; Modality; Neurons; Nociception; Pain; Patients; Perception; Peripheral; Pharmacology; Phenotype; Play; Property; Reporting; Resources; Risk; Rodent; Role; Sensory; Sigmoid colon; Sodium Channel; Spinal Ganglia; Stimulus; Structure of superior cervical ganglion; Symptoms; Techniques; Testing; Text; Therapeutic; Time; Ulcerative Colitis; Variant; Visceral; Visceral pain; chronic abdominal pain; cohort; experience; genetic variant; genotyped patients; inflammatory disease of the intestine; insight; mutant; novel; novel diagnostics; novel therapeutic intervention; pain perception; pain reduction; pain score; pain signal; patient screening; pressure; rectal; research clinical testing; somatosensory; targeted exome sequencing; tool; transmission process; voltage

Managing disorders associated with altered perception of abdominal pain remains a major challenge in healthcare. This is particularly true with silent inflammatory bowel disease (IBD), a condition in which individuals with active disease experience little to no concomitant abdominal pain. Silent IBD is common, affecting a third or more of these patients, and can be seen in both major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC). Silent IBD is also very impactful, as these individuals are more than twice as likely to develop serious complications (including strictures, fistulae and abscesses) and to be hospitalized. Unfortunately, currently available diagnostic strategies are limited due to inefficacy, expense and/or practicality. A refined understanding of the mechanisms underlying silent IBD would allow us to develop more effective methods to screen for patients at risk for this condition and could provide insight into novel targets that could be utilized to manage conditions associated with chronic abdominal pain. There is evidence to suggest that voltage-gated sodium channels (VGSC’s) could play a particularly critical role in the development of silent IBD. Previous studies have implicated certain subtypes of these channels as major contributors to transmission of peripheral somatosensory and visceral pain signals. Using targeted exome sequencing in a small IBD cohort, we found that homozygosity for one genetic variant of Nav1.8 (rs6795970; G>A; A1073V) was more common in silent IBD patients. This is notable as one prior study linked this particular polymorphism to hyposensitivity to somatosensory pain stimuli. We hypothesize that Nav1.8 is critical for mediating visceral pain perception and that rs6795970 leads to its dysfunction, resulting in an anti-nociceptive phenotype in IBD. In order to test this hypothesis, we propose to: a) evaluate the frequency of the polymorphism, rs6795970, within larger cohorts of healthy controls, CD and UC patients phenotyped for pain and disease activity, b) assess for changes in visceral and somatic sensation associated with this polymorphism, using barostatic rectal distension and quantitative sensory testing techniques, and c) evaluate for changes in biophysical function of intestinal sensory afferent neurons and pharmacological function of sensory neuron derived cells expressing the mutant channel associated with this polymorphism. These studies are essential as they could identify an objective biomarker to identify patients at risk of developing silent IBD and may provide critical insight into new diagnostic and therapeutic strategies to manage disorders associated with alterations of abdominal pain.

管理与腹痛感知改变相关的疾病仍然是医疗保健中的一个重大挑战，对于无症状炎症性肠病 (IBD) 来说尤其如此，患有活动性疾病的人很少或没有伴随无症状 IBD 的情况很常见。影响其中三分之一或更多的患者，并且可以在两种主要形式的 IBD、克罗恩病 (CD) 和溃疡性结肠炎 (UC) 中看到，其影响也非常大，因为这些患者患上 IBD 的可能性是其两倍以上。严肃的不幸的是，由于无效、费用和/或实用性，目前可用的诊断策略是有限的。筛选有这种疾病风险的患者，并可以深入了解可用于治疗慢性腹痛相关疾病的新靶标。有证据表明，电压门控钠通道（VGSC）可能在慢性腹痛中发挥特别关键的作用。发展先前的研究表明这些通道的某些亚型是外周体感和内脏疼痛信号传输的主要贡献者。在一个小型 IBD 队列中使用靶向外显子组测序，我们发现 Nav1.8 的一种遗传变异（rs6795970；rs6795970）具有纯合性。 G>A；A1073V）在无症状 IBD 患者中更为常见，这一点值得注意，因为之前的一项研究将这种特殊的多态性与过敏性低下联系起来。我们相信 Nav1.8 对于介导内脏疼痛感知至关重要，而 rs6795970 会导致其功能障碍，从而导致 IBD 中的抗伤害性表型。 b) 评估疼痛和疾病活动表型的健康对照、CD 和 UC 患者的较大队列中多态性 rs6795970 的频率，b) 评估使用直肠扩张和定量感觉测试技术，评估与该多态性相关的内脏和躯体感觉，以及c)评估肠道感觉传入神经元的生物物理功能的变化以及表达与该多态性相关的突变通道的感觉神经元衍生细胞的药理学功能。这些研究至关重要，因为它们可以确定客观的生物标志物来识别有患无症状IBD风险的患者，并可能为控制与腹痛改变相关的疾病的新诊断和治疗策略提供重要见解。