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

描述（由申请人提供）：压力和免疫系统是身体对身心和致病挑战的防御机制。应激反应的主要介质有：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、趋化因子和细胞粘附分子介导的。然而，在慢性应激或不受控制的炎症条件下，这些适应系统变得不适应。外周器官（如胃肠道）细胞长期暴露于这些介质会改变关键细胞蛋白的基因表达，导致其功能改变和症状性疾病。在这方面，促炎细胞因子长期暴露于结肠循环平滑肌细胞抑制Cav1.2 （l型）钙通道的表达，导致Ca2+内流减少和细胞收缩性降低。慢性应激介质对结肠平滑肌细胞基因表达改变的影响和机制尚未研究。此外，慢性应激介质和炎症介质之间的相互作用加剧或沉淀结肠循环平滑肌功能障碍尚不清楚。我们的假设是：1)慢性应激介质改变结肠环状平滑肌细胞（RCCSMCs）兴奋-收缩耦合关键信号蛋白的基因表达。这种慢性应激介质的转录作用导致平滑肌对乙酰胆碱的超敏反应和更快的结肠转运；2)当慢性应激和炎症同时发生或相继发生时，应激介质和免疫介质之间的细胞相互作用加剧或加剧了结肠运动功能障碍。因此，本提案的具体目的是：1)确定慢性应激的介质或介质，改变RCCSMCs中特定细胞信号蛋白的基因表达，导致平滑肌超敏反应；2)研究细胞信号通路和转录机制，诱导关键信号蛋白的基因表达，以响应特定目的1中确定的慢性应激介质或介质；3)研究慢性应激介质在并发或连续慢性应激和炎症损伤下加剧或沉淀结肠平滑肌功能障碍的机制。众所周知，慢性应激可加重或加速炎症性肠病和肠易激综合征患者的结肠运动功能障碍症状。这一发现有望确定潜在的分子治疗方法，以预防或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.