CORRELATION BETWEEN STRUCTURAL AND MOTOR DEFECTS IN DIABETIC GASTROPARESIS

糖尿病胃轻瘫结构性缺陷和运动缺陷之间的相关性

• 批准号: 8360516
• 负责人: Grant Hennig
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360516
• 关键词: Affect; Antral; Area; Behavior; CCL4 gene; Centers of Research Excellence; Defect; Deterioration; Diabetic mouse; Diffusion; Dyes; Effectiveness; Functional disorder; Funding; Gastroparesis; Grant; Hospitalization; Image; Imaging technology; Interstitial Cell of Cajal; Lesion; Life Style; Measures; Motor; Motor Activity; Mus; National Center for Research Resources; Nerve; Nerve Endings; Nerve Fibers; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Patients; Pattern; Peristalsis; Principal Investigator; Pyloric antrum; Recommendation; Research; Research Infrastructure; Resolution; Resources; Smooth Muscle; Source; Stomach; Structure; Transgenic Mice; United States National Institutes of Health; autonomic neuropathy; cost; density; diabetic gastroparesis; diet and exercise; mouse model; multi-photon; novel; prevent; sensor; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gastroparesis, or delayed gastic emptying, occurs in approximately one third of patients with Type 2 diabetes mellitus (T2DM). While rarely fatal, it can cause serious nutritional complications that often require hospitalization. Vagal and autonomic neuropathy are commonly cited as the main causes of gastroparesis, however recent evidence suggests that interstitial cells of Cajal (ICC) may be involved. What is not known is how lesions in ICC networks cause gastric motor behavior to become abnormal. Two classes of ICC are found in the stomach and are responsible for 1) generating and conducting slow waves (ICC-MY) that produce antral peristalsis, and 2) acting as intermediaries between motor nerve ending and smooth muscle (ICC-IM). In this proposal we will investigate whether the pattern of deterioration of the ICC-MY network correlates to specific gastric dysrhythmias observed in T2DM. We will also investigate if damage or loss of intermediary ICC-IM reducers the effectiveness of motor transmission. A number of novel transgenic mice and advanced imaging technologies have recently become available that will allow a precise examination of changes in the structure of ICC networks to be correlated to motor dysfunctions. We will first observe and record motor abnormalities in the gastric antrum of mouse models of T2DM, then perform high resolution imaging in areas which showed abnormal motor activity and measure changes in the structure and density of ICC in the ICC-MY network. Ca2+ imaging and novel Ca2+ sensor expressing mice will allow us to explore changes that may be occurring at the cellular level of the ICC-MY network in T2DM mice. Using nerve stimulation we will examine which type of motor transmission is affected in T2DM mice, then using confocal and multi-photon confocal imaging, examine structural changes that occur between motor nerve fibers and ICC-IM that may indicate an unraveling of their normally close relationship. Using novel indicator dyes, we can directly observe the release and diffusion of the inhibitory neurotransmitter NO, and examine any dysfunctions. The most common recommendation for patients with T2DM is lifestyle changes involving diet and exercise. We will investigate whether these recommendations can prevent gastric motor abnormalities from occurring in diabetic mice, or whether gastric motor activity can be restored after damage has occurred in T2DM. Results from this study will determine if loss of ICC are responsible for gastroparesis.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 大约三分之一的 2 型糖尿病 (T2DM) 患者会出现胃轻瘫或胃排空延迟。虽然很少致命，但可能会导致严重的营养并发症，通常需要住院治疗。迷走神经和自主神经病变通常被认为是胃轻瘫的主要原因，但最近的证据表明卡哈尔间质细胞 (ICC) 可能参与其中。目前尚不清楚 ICC 网络的病变如何导致胃运动行为异常。胃中发现两类 ICC，负责 1) 产生和传导慢波 (ICC-MY)，从而产生胃窦蠕动；2) 充当运动神经末梢和平滑肌 (ICC-IM) 之间的中介。在本提案中，我们将研究 ICC-MY 网络的恶化模式是否与 T2DM 中观察到的特定胃节律失常相关。我们还将调查中间 ICC-IM 的损坏或丢失是否会降低运动传输的有效性。最近出现了许多新型转基因小鼠和先进的成像技术，可以精确检查与运动功能障碍相关的 ICC 网络结构的变化。我们将首先观察并记录T2DM小鼠模型胃窦的运动异常，然后对运动活动异常的区域进行高分辨率成像，并测量ICC-MY网络中ICC的结构和密度的变化。 Ca2+ 成像和新型 Ca2+ 传感器表达小鼠将使我们能够探索 T2DM 小鼠 ICC-MY 网络细胞水平可能发生的变化。使用神经刺激，我们将检查 T2DM 小鼠中哪种类型的运动传输受到影响，然后使用共焦和多光子共焦成像，检查运动神经纤维和 ICC-IM 之间发生的结构变化，这可能表明它们通常密切的关系正在瓦解。使用新型指示剂染料，我们可以直接观察抑制性神经递质NO的释放和扩散，并检查任何功能障碍。对 T2DM 患者最常见的建议是改变生活方式，包括饮食和锻炼。我们将研究这些建议是否可以防止糖尿病小鼠发生胃运动异常，或者在 T2DM 发生损伤后胃运动活动是否可以恢复。这项研究的结果将确定 ICC 的丧失是否会导致胃轻瘫。