Alpha-2 Adrenergic Control of Colonic Function in IBS

Alpha-2 肾上腺素能控制 IBS 结肠功能

• 批准号: 6936670
• 负责人: MICHAEL L. CAMILLERI
• 金额: $ 24.09万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936670
• 关键词: African American; alpha adrenergic agent; alpha adrenergic receptor; autonomic nervous system; clinical research; clonidine; drug screening /evaluation; gastrointestinal disorder chemotherapy; gastrointestinal motility /pressure; gene expression; human subject; human therapy evaluation; irritable bowel syndrome; neuroregulation; pain threshold; single photon emission computed tomography

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a common condition with high impact on quality of life, health care costs, and incidence of abdominal or pelvic surgery. Two pathophysiological mechanisms in IBS are heightened visceral sensitivity and/or abnormal motor function. We have previously shown that the adrenergic nervous system is involved in modulating gastrointestinal functions in healthy humans and in IBS. Specifically, in the previous cycle of this grant, we demonstrated that clonidine, an alpha2-adrenergic agonist, relaxes the colon, reduces sensations of gas and pain during distention, without impacting on the normal rate of transit through the entire gut, or inhibiting the effect of meal ingestion on colonic motility. Secondly, we demonstrated that clonidine, 0.1 mg b.i.d., improved bowel dysfunction and provided satisfactory relief of IBS in a subgroup of patients. Subgroups with high vs. no response to clonidine in IBS patients suggest a role for adrenergic genotypes in determining the response in patients. In preliminary studies in Caucasian patients with diarrhea-predominant IBS, we have identified an alpha2c adrenoreceptor NciI polymorphism (located in the region coding for the third intracellular loop of the receptor) with a higher allele frequency (0.33) than in ethnic controls (0.04). Accurate, thorough phenotypic characterization of patients with IBS and their responses to clonidine are essential for pharmacogenomic studies. Our overall objective is to characterize in IBS patients the relationship between the phenotypic response to elonidine and genetic variations in noradrenergic and alpha2-adrenergic control using a candidate gene analysis approach. We hypothesize that: 1) physiological studies of whole gut transit, gastric volume and response to feeding, rectal sensory and motor functions, and cerebral and peripheral sympathetic function will characterize the phenotype of different symptom-based subgroups of IBS patients; 2) patients with sympathetic adrenergic dysfunction are more sensitive to the effects of 0.1mg and 0.15 mg clonidine on physiological measurements of gut function; and 3) polymorphisms of the alpha2A-and alpha2c adrenoreceptor genes or mutations in norepinephrine transporter (NET) protein influence the physiological (motor and sensory) responses to clonidine. Our first aim is to characterize whole gut transit, rectal sensory and motor functions, gastric volumes, postprandial abdominal symptoms and central and peripheral adrenergic functions in 120 patients with IBS and 40 controls. Secondly, we aim to study the effects of acute administration of 0.1 or 0.15 mg clonidine (p.o.) on the same gastrointestinal functions in IBS patients and controls. Our third aim is to assess the relationship between the responses of physiological sensory and motor gut parameters to clonidine and polymorphisms of the alpha2A-and alpha2c-adrenergic receptors on chromosomes 2 and 10 and mutations in the gone encoding the NET protein. A fourth aim will assess the feasibility of recruiting African- American IBS patients from other medical centers to obtain preliminary data on symptom phenotype and adrenergic genotype in these patients and their community controls. The significance of this project is that it will provide novel, comprehensive information on the symptom and physiological phenotype of different subgroups of IBS, and characterize the pharmacogenetic mechanisms determining the response to clonidine through studies of candidate genes that control ?2-adrenoreceptor function and norepinephrine transport in IBS.

描述（由申请人提供）：肠易激综合症（IBS）是一种常见状况，对生活质量，医疗保健成本以及腹部或骨盆手术的发病率很高。 IBS中的两种病理生理机制是内脏敏感性和/或异常运动功能的提高。我们以前已经表明，肾上腺素能神经系统参与调节健康人类和IBS中的胃肠道功能。具体而言，在该赠款的上一个周期中，我们证明了α2-肾上腺素能激动剂可乐定放宽结肠，减少延伸过程中气体和疼痛的感觉，而不会影响整个肠道的正常过境速率，或者抑制饮食摄入量对结肠运动的影响。其次，我们证明了可乐定为0.1 mg B.I.D.，改善了肠功能障碍，并在患者亚组中提供了令人满意的IBS。 IBS患者中对可乐定的反应的亚组表明，肾上腺素能基因型在确定患者的反应中起作用。在对高加索腹泻前体IBS患者的初步研究中，我们已经鉴定出具有比种族控制频率更高（0.04）（0.04）的α2C肾上腺肾上腺受体NCII多态性（位于受体第三个细胞内环的区域）。 IBS患者的准确，彻底的表型表征及其对可乐定的反应对于药物基因组学研究至关重要。我们的总体目的是在IBS患者中表征对去甲肾上腺素的表型反应与使用候选基因分析方法对去甲肾上腺素和α2-肾上腺素能控制的遗传变异之间的关系。我们假设：1）整个肠道过境，胃体积以及对喂养，直肠感觉和运动功能的反应以及脑和周围交感神经功能的生理研究将表征IBS患者基于不同症状的亚组的表型； 2）交感神经功能障碍患者对0.1mg和0.15 mg可乐定对肠功能的生理测量的影响更敏感； 3）α2A和α2C肾上腺素受体基因或去甲肾上腺素转运蛋白（NET）蛋白突变的多态性影响对可乐定的生理（运动和感觉）反应。我们的第一个目的是表征整个肠道传输，直肠感觉和运动功能，胃量，餐后腹部症状以及120例IBS患者和40例对照患者的中心和周围肾上腺素能功能。其次，我们旨在研究0.1或0.15 mg可乐定（P.O.）急性给药对IBS患者和对照组中相同胃肠道功能的影响。我们的第三个目的是评估生理感觉和运动肠道参数对可乐定的反应与染色体2和10上的α2C-肾上腺素能受体的α2A和α2C-肾上腺素能受体的多态性与突变之间的关系之间的关系。第四个目标将评估来自其他医疗中心的非裔美国IBS患者的可行性，以获取有关这些患者及其社区对照组中症状表型和肾上腺素能基因型的初步数据。该项目的意义在于，它将提供有关IBS不同亚组的症状和生理表型的新颖，全面的信息，并通过对控制IBS中的2-肾上腺受体功能和去甲肾上腺素转运的候选基因的研究来确定对可乐定基因的反应的药物遗传学机制。