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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 大约三分之一的2型糖尿病患者（T2DM）发生了胃轻瘫或延迟的加斯流空排空。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。迷走神经和自主神经病通常被认为是胃肉食的主要原因，但是最近的证据表明，Cajal（ICC）的间质细胞可能涉及。尚不清楚的是ICC网络中的病变如何导致胃运动行为变得异常。在胃中发现了两类的ICC，并负责1）产生和传导慢波（ICC-MY），产生鼻蠕动，2）在运动神经结束和平滑肌（ICC-IM）之间用作中间体（ICC-IM）。在此提案中，我们将研究ICC-MY网络恶化的模式是否与在T2DM中观察到的特定胃动力学不动性相关。我们还将调查中介ICC-IM的损坏或损失是否降低了电动机传输的有效性。最近已经获得了许多新型的转基因小鼠和高级成像技术，可以精确检查ICC网络结构的变化与运动功能障碍相关。我们将首先观察和记录T2DM小鼠模型胃胃肠道中的运动异常，然后在ICC-MY网络中ICC的结构和密度变化的区域进行高分辨率成像。 CA2+成像和表达小鼠的新型Ca2+传感器将使我们能够探索T2DM小鼠ICC-MY网络的细胞水平可能发生的变化。使用神经刺激，我们将检查T2DM小鼠中哪种运动类型的传播类型，然后使用共聚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，这可能表明其正常紧密的关系。使用新型指标染料，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。针对T2DM患者的最常见建议是涉及饮食和运动的生活方式改变。我们将调查这些建议是否可以防止糖尿病小鼠中发生胃运动异常，或者在T2DM中损坏后是否可以恢复胃运动活动。这项研究的结果将确定ICC的丧失是否负责胃轻瘫。