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: 8009516
• 负责人: SUSHIL K SARNA
• 金额: $ 29.6万
• 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/8009516
• 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; TNF gene; 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）：压力和免疫系统是身体对心身和病原体挑战的防御机制。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。炎症反应由细胞因子、趋化因子和细胞粘附分子介导。然而，在慢性应激或不受控制的炎症条件下，这些适应系统变得适应不良。外周器官（如胃肠道）的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环形平滑肌细胞抑制Cav1.2（L型）钙通道的表达，导致Ca 2+内流和细胞收缩性降低。当暴露于慢性应激介质时，结肠平滑肌细胞中基因表达改变的影响或机制尚未研究。此外，慢性应激介质和炎症介质之间的相互作用加剧或加速结肠环形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形平滑肌细胞（RCCSMC）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作用导致平滑肌对ACh的超敏反应和结肠中更快的转运;和2）当慢性应激和炎性损伤同时或相继发生时，应激介质和免疫介质之间的细胞相互作用加剧或加速结肠运动功能障碍。因此，本发明的具体目的是：1）鉴定改变RCCSMC中特定细胞信号蛋白的基因表达的慢性应激的一种或多种介质，从而导致平滑肌超敏; 2）研究细胞信号传导途径和转录机制，所述细胞信号传导途径和转录机制诱导关键信号传导蛋白的基因表达以响应特定目标1中鉴定的慢性应激的一种或多种介质，和3）研究慢性应激介质加重或加速由于同时或相继的慢性应激和炎症损伤引起的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重炎症性肠病和肠易激综合征的结肠动力功能障碍症状。本研究的结果有望发现潜在的分子治疗方法，可以预防或减少慢性应激对结肠运动功能的不良影响。