Role of clock genes in colonic motility

时钟基因在结肠运动中的作用

• 批准号: 8011281
• 负责人: CHUNG OWYANG
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011281
• 关键词: Abdomen; Abdominal Pain; Acetylcholine; Address; Affect; Biological Rhythm; Brain; Colon; Constipation; Cues; Data; Defecation; Development; Diarrhea; Environment; Enzymes; Feces; Functional disorder; Gastrointestinal Physiology; Gene Expression; Genes; Genus Cola; Goals; Hour; Human; Individual; Intervention; Intracolonic; Knockout Mice; Lasers; Lead; Liver; Methods; Microscopy; Monitor; Mus; Myenteric Plexus; Neurotransmitters; Nitric Oxide; Organ; Pathogenesis; Pathway interactions; Pattern; Peripheral; Physiological; Physiological Adaptation; Play; Regulation; Research Personnel; Role; Site; Stimulus; Time; Tissues; Travel; cell motility; design; environmental change; feeding; feeding schedule; gastrointestinal; gastrointestinal symptom; light effects; motility disorder; pressure; programs; response; shift work; suprachiasmatic nucleus

DESCRIPTION (provided by applicant): Humans have bowel movements during the day, frequently following awakening or following a meal but rarely during the night. In line with this observation are ambulatory pressure recordings demonstrating maximal colonic activity during the day. Thus colonic motility follows a rhythm. Disruption of our daily rhythm such as occurs with shift work or time zone traveling, is associated with gastrointestinal symptoms. These observations suggest a functional correlation between our daily rhythm and gastrointestinal physiology. Biological rhythms are controlled by clock genes. A central clock is located in the brain. However, clock genes are present in peripheral organs as well. Within peripheral organs, clock genes control the expression of a subset of tissue-specific genes, thereby directly affecting physiological function. Clock genes can synchronize themselves to external time cues such as the light/dark cycle and feeding. Our preliminary data show expression of clock genes in the murine colon. This expression is rhythmic and increases at the start of the dark cycle. Along with this, enzymes involved in the synthesis of the colonic neurotransmitters acetylcholine and nitric oxide increase at the onset of the dark cycle. Moreover, we show that mice pass an increased number of stool pellets at night. This is associated with increased nocturnal intracolonic pressure activity, as assessed by a newly developed method for prolonged intracolonic pressure monitoring in freely moving mice. We show colonic clock gene expression in the myenteric plexus, an important site of neurotransmitter synthesis. Taken together, the data suggest that the colon may have a time-keeping capability that allows for the physiological adaptation of colonic motility to environmental stimuli. We hypothesize that changes in the light/dark cycle and feeding schedule affect colonic motility through clock genes. The overall goal of our studies are to determine the effect of changes in light/dark cycle and feeding schedule on clock gene expression, neurotransmitter synthesizing enzyme expression and colonic motility in wildtype and clock gene (PER1/PER2) knockout mice. To this extent we will use laser capture microscopy, real-time PCR and colonic motility studies. This proposal will establish whether clock genes play a role in colonic motility. This is important, as gastrointestinal dysfunction is a common complaint of time-zone travelers and shift workers. We speculate that the gastrointestinal symptoms of those individuals result from the inability of clock genes to make timely adjustments to changes in environmental cues. The long-term goal for this project is to develop a better understanding of the role of clock genes in colonic motility, the pathways participating in the entrainment of colonic clock genes, their role in dysmotility syndromes and eventually, the development of pharmacological interventions that will enhance the synchronization of clock genes to changes in the environment.

描述（由申请人提供）：人类在白天排便，经常在醒来后或饭后排便，但很少在夜间排便。与这一观察结果一致的是动态压力记录，显示白天最大结肠活动。因此，结肠运动遵循一定的节律。轮班工作或时区旅行等扰乱我们的日常节奏，与胃肠道症状有关。这些观察结果表明我们的日常节律和胃肠道生理学之间存在功能相关性。生物节律由时钟基因控制。中央时钟位于大脑中。然而，时钟基因也存在于外周器官中。在外周器官内，时钟基因控制组织特异性基因子集的表达，从而直接影响生理功能。时钟基因可以将自身与外部时间线索同步，例如光/暗周期和进食。我们的初步数据显示时钟基因在小鼠结肠中的表达。这种表达是有节奏的，并在黑暗周期开始时增加。与此同时，参与结肠神经递质乙酰胆碱和一氧化氮合成的酶在暗周期开始时增加。此外，我们发现小鼠在夜间排出的粪便颗粒数量增加。这与夜间结肠内压力活动增加有关，这是通过新开发的对自由活动的小鼠进行长时间结肠内压力监测的方法进行评估的。我们展示了结肠时钟基因在肌间丛中的表达，肌间丛是神经递质合成的重要部位。综上所述，数据表明结肠可能具有计时能力，允许结肠运动对环境刺激进行生理适应。我们假设光/暗周期和进食时间表的变化通过时钟基因影响结肠运动。我们研究的总体目标是确定光/暗周期和喂养时间表的变化对野生型和时钟基因 (PER1/PER2) 敲除小鼠中时钟基因表达、神经递质合成酶表达和结肠运动的影响。为此，我们将使用激光捕获显微镜、实时 PCR 和结肠运动研究。该提案将确定时钟基因是否在结肠运动中发挥作用。这很重要，因为胃肠功能障碍是时区旅行者和轮班工人的常见抱怨。我们推测这些人的胃肠道症状是由于生物钟基因无法及时调整环境线索的变化造成的。该项目的长期目标是更好地了解时钟基因在结肠运动中的作用、参与结肠时钟基因夹带的途径、它们在运动障碍综合征中的作用，并最终开发药物干预措施增强时钟基因与环境变化的同步性。

项目成果

Role of biological rhythms in gastrointestinal health and disease.

生物节律在胃肠道健康和疾病中的作用。

• 发表时间: 2009-12
• 影响因子: 8.2
• 作者: Hoogerwerf; Willemijntje A
• 通讯作者: Willemijntje A

Role of clock genes in gastrointestinal motility.

时钟基因在胃肠运动中的作用。

• DOI: 10.1152/ajpgi.00147.2010
• 发表时间: 2010-06-17
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: W. Hoogerwerf

Rhythmic changes in colonic motility are regulated by period genes.

结肠运动的节律变化受周期基因调节。

• DOI: 10.1152/ajpgi.00402.2009
• 发表时间: 2010-02-01
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: W. Hoogerwerf;V. Shahinian;G. Cornelissen;F. Halberg;J. Bostwick;J. Timm;P. Bartell;V. Cassone
• 通讯作者: V. Cassone

Effects of acute and chronic STZ-induced diabetes on clock gene expression and feeding in the gastrointestinal tract.

急性和慢性 STZ 诱导的糖尿病对胃肠道时钟基因表达和喂养的影响。

• 发表时间: 2010-05
• 影响因子: 4.3
• 作者: Bostwick, Jonathon;Nguyen, Diane;Cornélissen, Germaine;Halberg, Franz;Hoogerwerf, Willemijntje A
• 通讯作者: Hoogerwerf, Willemijntje A

Clock gene expression in the murine gastrointestinal tract: endogenous rhythmicity and effects of a feeding regimen.

• DOI: 10.1053/j.gastro.2007.07.009
• 发表时间: 2007-10-01
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: W. Hoogerwerf;H. Hellmich;G. Cornelissen;F. Halberg;V. Shahinian;J. Bostwick;T. Savidge;V. Cassone
• 通讯作者: V. Cassone