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.

管理与腹痛看法改变有关的疾病仍然是医疗保健的主要挑战。沉默的炎症性肠病（IBD）尤其如此，在这种情况下，患有活动疾病的人几乎没有腹痛。无声的IBD很常见，影响了这些患者的三分之一或更多，并且可以在IBD，克罗恩病（CD）和溃疡性结肠炎（UC）中看到。 IBD也非常有影响力，因为这些人出现严重的并发症（包括狭窄，瘘管和脓肿）的可能性是两倍以上。不幸的是，由于效率低下，费用和/或实践，目前可用的诊断策略受到限制。对无声IBD背后的机制的精致理解将使我们能够开发出更有效的方法来筛选有这种情况风险的患者，并可以洞悉可用于管理与慢性腹痛相关的疾病的新型靶标。有证据表明，电压门控钠通道（VGSC）可能在静音IBD的发展中起特别关键的作用。先前的研究已经实施了这些渠道的某些亚型，是外周体感和内脏疼痛信号传播的主要因素。在小型IBD队列中使用靶向外显子组测序，我们发现一种NAV1.8（RS6795970; g> a; a1073v）的遗传变异的纯合性在无声的IBD患者中更为普遍。这是一项先前的研究值得注意的，将这种特殊的多态性与体感疼痛刺激联系起来。我们假设NAV1.8对于介导内脏疼痛感知至关重要，并且6795970导致其功能障碍，从而导致IBD中的抗吸引感性表型。为了检验这一假设，我们建议：a）在较大的健康对照组中评估多态性的频率，rs6795970，CD和UC患者在疼痛和疾病活动中表现出了CD和UC患者，b）评估与内脏和体育疗法的变化相关的变化，并评估了与骨化的探测器的变化，并评估了骨化剂量的变化，以孔隙率依从剂的变化，以孔隙率的变化技术，以进行重质性差异技术，以实现重度质量差异技术，以均匀的态度变化，以实现重度依赖性的技术，并将其置于重度依赖性技术方面的变化。肠道感觉传入神经元的生物物理功能以及表达与该多态性相关的突变通道的感觉神经元的药理功能。这些研究至关重要，因为它们可以识别出客观的生物标志物，以鉴定出患有静音IBD风险的患者，并可能对新的诊断和治疗策略进行批判性见解，以管理与腹痛改变有关的疾病。