Chronic stress-induced gene expression in colonic circular smooth muscle cells.

描述(申请人提供)：压力和免疫系统是人体对心身和病原体挑战的防御机制。应激反应的主要介质是：促肾上腺皮质激素释放激素、去甲肾上腺素、糖皮质激素和自主神经系统的神经递质。炎症反应是由细胞因子、趋化因子和细胞黏附分子介导的。然而，在慢性应激或炎症失控的情况下，这些适应系统会变得不适应。胃肠道等外周器官的细胞长期暴露在这些介质中会改变关键细胞蛋白的基因表达，导致它们的功能改变和症状性疾病。在这一点上，促炎细胞因子长时间暴露于结肠环状平滑肌细胞，抑制了Cav1.2(L类型)钙通道的表达，导致钙离子内流减少，细胞收缩。当暴露于慢性应激介质时，结肠平滑肌细胞基因表达改变的影响或机制尚未被研究。此外，慢性应激的介质和炎症介质之间的相互作用加剧或加速结肠环状平滑肌功能障碍尚不清楚。我们的假设是：1)慢性应激介质改变了结肠环状平滑肌细胞(RCCSMCs)兴奋-收缩偶联关键信号蛋白的基因表达。慢性应激介质的这种转录效应导致平滑肌对ACh超敏和在结肠中更快的运输；以及2)应激介质和免疫介质之间的细胞相互作用，当慢性应激和炎性损伤同时或顺序发生时，加剧或加速结肠动力功能障碍。因此，这项建议的具体目的是：1)确定慢性应激的一个或多个介体，改变RCCSMCs中特定细胞信号蛋白的基因表达，从而导致平滑肌超敏反应；2)研究诱导关键信号蛋白基因表达的细胞信号通路和转录机制，以响应特定目标1中确定的一个或多个慢性应激介体；以及3)研究慢性应激介体加重或加速慢性应激和炎性侮辱所致的结肠平滑肌功能障碍的机制。众所周知，在炎症性肠病和肠易激综合征中，慢性应激会加剧或加速结肠动力障碍的症状。这项建议的发现有望确定潜在的分子治疗方法，以防止或最大限度地减少慢性应激对结肠运动功能的不良影响。

DESCRIPTION (provided by applicant): Stress and immune systems are a body's defense mechanisms against psychosomatic and pathogenic challenges. The primary mediators of the stress response are: corticotropin releasing hormone, norepinephrine, glucocorticoids and the neurotransmitters of the autonomic nervous system. The inflammatory response is mediated by cytokines, chemokines and cell adhesion molecules. However, under conditions of chronic stress or uncontrolled inflammation, these adaptive systems become maladaptive. The prolonged exposure of the cells of the peripheral organs, such as the gastrointestinal tract, to these mediators alters the gene expression of key cellular proteins, leading to alteration of their function and symptomatic disease. In this regard, the prolonged exposure of proinflammatory cytokines to colonic circular smooth muscle cells suppress the expression of Cav1.2 (L-type) calcium channels, leading to reduced Ca2+ influx and cell contractility. The effects or mechanisms of altered gene expression in colonic smooth muscle cells when exposed to chronic stress mediators have not been investigated yet. Also, the interactions between the mediators of chronic stress and those of inflammation to exacerbate or precipitate colonic circular smooth muscle dysfunction are not known. Our hypotheses are: 1) The mediators of chronic stress alter the gene expression of critical signaling proteins for excitation-contraction coupling in colonic circular smooth muscle cells (RCCSMCs). This transcriptional effect of chronic stress mediators results in smooth muscle hypersensitivity to ACh and faster transit in the colon; and 2) The cellular interactions between the stress mediators and immune mediators, when both chronic stress and inflammatory insults occur concurrently or sequentially exacerbate or precipitate colonic motility dysfunction. Accordingly, the specific aims of this proposal are to: 1) identify the mediator or mediators of chronic stress that alter gene expression of specific cell signaling proteins in RCCSMCs, resulting in smooth muscle hypersensitivity; 2) investigate the cell signaling pathways and transcriptional mechanisms that induce gene expression of key signaling proteins in response to the mediator or mediators of chronic stress identified in specific aim 1, and 3) to investigate the mechanisms by which chronic stress mediators exacerbate or precipitate colonic smooth muscle dysfunction due to concurrent or sequential chronic stress and inflammatory insults. Chronic stress is well known to exacerbate or precipitate the symptoms of colonic motility dysfunction in inflammatory bowel disease and irritable bowel syndrome. The findings of this proposal are expected to identify the potential molecular therapeutic approaches that may prevent or minimize the ill effects of chronic stress on colonic motility function.