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。

基本信息

批准号：
8208147
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208147
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

项目摘要

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针对心身和致病挑战的防御机制。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。炎症反应由细胞因子、趋化因子和细胞粘附分子介导。然而，在慢性压力或不受控制的炎症条件下，这些适应性系统会变得适应不良。胃肠道等外周器官的细胞长时间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，促炎细胞因子长时间暴露于结肠环形平滑肌细胞会抑制 Cav1.2（L 型）钙通道的表达，导致 Ca2+ 流入和细胞收缩力减少。尚未研究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。此外，慢性应激介质与炎症介质之间的相互作用是否会加剧或促进结肠环形平滑肌功能障碍尚不清楚。我们的假设是：1）慢性应激的介质改变了结肠圆形平滑肌细胞（RCCSMC）中兴奋-收缩耦合的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乙酰胆碱过敏并加快结肠中的转运； 2)当慢性应激和炎症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会加剧或促进结肠运动功能障碍。因此，该提案的具体目标是：1）确定慢性应激的介质或介质，这些介质会改变RCCSMC中特定细胞信号蛋白的基因表达，从而导致平滑肌过敏； 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 中确定的慢性应激介质，以及 3) 研究慢性应激介质加剧或促发结肠应激的机制由于并发或连续的慢性应激和炎症损伤而导致的平滑肌功能障碍。众所周知，慢性压力会加剧或加速炎症性肠病和肠易激综合征中结肠运动功能障碍的症状。该提案的研究结果有望确定潜在的分子治疗方法，可以预防或尽量减少慢性应激对结肠运动功能的不良影响。