CORRELATION BETWEEN STRUCTURAL AND MOTOR DEFECTS IN DIABETIC GASTROPARESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 大约三分之一的2型糖尿病（T2 DM）患者发生胃轻瘫或胃排空延迟。虽然很少致命，但它可能导致严重的营养并发症，往往需要住院治疗。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，然而最近的证据表明，Cajal间质细胞（ICC）可能参与其中。目前尚不清楚ICC网络的损伤如何导致胃运动行为异常。在胃中发现了两类ICC，它们负责1）产生和传导慢波（ICC-MY），产生胃窦扩张，以及2）充当运动神经末梢和平滑肌之间的中介（ICC-IM）。在本提案中，我们将研究ICC-MY网络的恶化模式是否与T2 DM中观察到的特定胃节律障碍相关。我们还将调查中介ICC-IM的损坏或丢失是否会降低电机传输的有效性。一些新的转基因小鼠和先进的成像技术最近已经成为可用的，这将允许精确检查的ICC网络的结构的变化与运动功能障碍。我们将首先观察和记录T2 DM小鼠模型胃窦的运动异常，然后在显示异常运动活动的区域进行高分辨率成像，并测量ICC-MY网络中ICC结构和密度的变化。Ca 2+成像和新型Ca 2+传感器表达小鼠将使我们能够探索T2 DM小鼠ICC-MY网络细胞水平可能发生的变化。使用神经刺激，我们将检查哪种类型的运动传递在T2 DM小鼠中受到影响，然后使用共聚焦和多光子共聚焦成像，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的密切关系正在瓦解。使用新的指示剂染料，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T2 DM患者最常见的建议是改变生活方式，包括饮食和运动。我们将研究这些建议是否可以预防糖尿病小鼠胃运动异常的发生，或者T2 DM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的丧失是否是胃轻瘫的原因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.