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

结肠环形平滑肌细胞中慢性应激诱导的基因表达。

• 批准号: 7753240
• 负责人: SUSHIL K SARNA
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753240
• 关键词: Abbreviations; Acetylcholine; Affect; Autonomic nervous system; Biological Response Modifiers; Cell Adhesion Molecules; Cells; Chronic stress; Colon; Corticotropin-Releasing Hormone; Coupling; Data; Defense Mechanisms; Disease; Enteral; Epithelial Cells; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Glucocorticoids; Health; Homeostasis; Hormones; Hypersensitivity; Immune response; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Irritable Bowel Syndrome; L-Type Calcium Channels; Life; Mediating; Mediator of activation protein; Molecular; Names; Neuroglia; Neurons; Neurotransmitters; Norepinephrine; Organ; Organism; Peripheral; Principal Investigator; Proteins; Psychophysiologic Disorders; Rattus; Recruitment Activity; Research; Sarna; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle; Smooth Muscle Myocytes; Stress; Symptoms; System; Therapeutic; Time; Tissues; base; biological adaptation to stress; cell motility; cell type; chemokine; coping; cytokine; prevent; programs; response

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.

描述（由申请人提供）：压力和免疫系统是人体对心理和致病挑战的防御机制。压力反应的主要介体是：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。但是，在慢性应激或不受控制的炎症条件下，这些适应性系统变得不良适应性。这些介体的细胞长时间暴露于外围器官（例如胃肠道），改变了钥匙细胞蛋白的基因表达，从而改变了其功能和症状性疾病。在这方面，促炎细胞因子长时间暴露于结肠圆形平滑肌细胞抑制了CAV1.2（L型）钙通道的表达，从而降低了Ca2+流入和细胞收缩力。暴露于慢性应激介质时，尚未研究结肠平滑肌细胞中基因表达改变的作用或机制。同样，尚不清楚慢性应激介质与炎症的介体之间的相互作用，以加剧或沉淀结肠圆形平滑肌功能障碍。我们的假设是：1）慢性应激的介体改变了临界信号传导蛋白的基因表达，以在结肠圆形平滑肌细胞（RCCSMC）中进行激发反应偶联。慢性应激介体的这种转录效应导致对ACH的平滑肌超敏反应，并在结肠中更快地转运。 2）当慢性应激和炎症性损伤同时或顺序加剧或沉淀结肠运动功能障碍时，应力介质与免疫介质之间的细胞相互作用。因此，该提案的具体目的是：1）确定RCCSMC中特定细胞信号蛋白的基因表达的慢性应激的介体或介体，从而导致平滑肌超敏反应； 2）研究细胞信号通路和转录机制，这些机制是针对特定目标中鉴定出的介质或慢性应激的介体或慢性应激的介体诱导基因表达的，而3）研究了慢性应激介体会导致结肠平滑肌功能障碍导致的结肠平滑压力障碍，导致结肠平滑的压力造成的机制，导致结肠平滑的压力或质量压力造成序列性或序列性的肌肉发作。众所周知，慢性应激会加剧或沉迷于炎症性肠病和肠易激综合征中结肠运动功能障碍的症状。预计该提案的发现将确定潜在的分子治疗方法，这些方法可能阻止或最大程度地减少慢性应激对结肠运动功能的不良影响。