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Epigenetic Pathways in Chronic Stress-associated Visceral Hyperalgesia

慢性应激相关内脏痛觉过敏的表观遗传途径

基本信息

批准号：
10248001
负责人：
SHUANGSONG HONG
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248001
关键词：
Abdominal Pain Animal Model Animals Applications Grants Biopsy Biopsy Specimen Brain Caco-2 Cells Cell Line Chronic stress Clinical Colon Comparative Study Corticosterone DNA Methylation Data Diarrhea Down-Regulation Epigenetic Process Epithelial Epithelial Cells Epithelium Female Functional disorder Gene Expression Gene Proteins Genes Genetic Transcription Glucocorticoid Receptor Goals Habits Histones Human Hydrocortisone Hyperalgesia IL6 gene In Vitro Inflammatory Interleukin-1 Interleukin-6 Intestines Irritable Bowel Syndrome Link Mediating Methods Methylation Modeling Modification Molecular Neural Pathways Neurons Nociception Nucleic Acid Regulatory Sequences Pathway interactions Patients Peripheral Permeability Play Preparation Proteins Rattus Regulation Regulator Genes Reporting Role Signal Transduction Spinal Ganglia TNF gene Testing Thinking Tight Junctions Time Visceral Visceral pain base biological sex claudin-1 protein cohort cytokine experimental study gene repression histone modification hypothalamic-pituitary-adrenal axis in vivo in vivo Model innovation intestinal barrier intestinal epithelium male monolayer new therapeutic target novel novel marker occludin pain perception potential biomarker prevent promoter protein expression response therapeutic target transcription factor

项目摘要

Project Abstract Chronic stress is commonly associated with enhanced abdominal pain (visceral hyperalgesia) and altered bowel habits in humans with Irritable Bowel Syndrome (IBS) and validated animal models via activation of the HPA-axis and the glucocorticoid receptor (GR) transcription factor. The cellular and molecular mechanisms underlying chronic stressed-associated visceral hyperalgesia are poorly understood; however, emerging evidence indicates that the visceral hyperalgesia is linked to decreased expression of colon epithelial cell tight junction proteins and increased paracellular permeability. Our lab and others have reported a potentially significant role for epigenetic mechanisms in nociceptive neural pathways in chronic stress-induced visceral hyperalgesia. It is unknown whether epigenetic mechanisms are directly involved in the decreased expression in intestinal epithelial tight junction proteins, increased paracellular permeability and visceral hyperalgesia. In this proposal, we provide compelling preliminary data supporting the novel hypothesis that methylation of repressive histone H3K9 plays a pivotal role in chronic stress- and pro-inflammatory cytokine-mediated visceral hyperalgesia via down-regulation in colon epithelial tight junction proteins and increased paracellular permeability using two validated rat models (males and females) and patients with diarrhea-prone IBS (males and females), differentiated human Caco-2 cells, human-derived colonoids and human-derived colon epithelial cell monolayers. We will examine the following vertically-integrated specific aims to confirm the role of H3K9me2/me3 in the pathophysiology of chronic stress-associated visceral hyperalgesia: Specific Aim 1: Test the global hypothesis that methylation of the repressive histone H3K9 plays a key role in chronic stress- induced intestinal barrier dysfunction and visceral hyperalgesia using two validated male animal models; Specific Aim 2: Examine how H3K9 methylation regulates intestinal epithelial tight junction gene transcription and protein expression, paracellular permeability and visceral hyperalgesia in response to chronic stress, corticosterone and pro-inflammatory cytokines; and Specific Aim 3: Assess the translatability of the animal studies to the human and potential differences based on biological sex. The application is highly significant because of the clinical importance of chronic stress to enhance visceral pain and the novel global hypothesis, innovative because of the use of state-of-art methods to study the global hypothesis in a systematic manner and high impact because of the potential to influence current thinking in the field.

项目摘要慢性应激通常与增强的腹痛（内脏痛觉过敏）和改变的肠易激综合征（IBS）患者的排便习惯以及通过激活 HPA轴和糖皮质激素受体（GR）转录因子。的细胞和分子机制潜在的慢性应激相关内脏痛觉过敏知之甚少;然而，有证据表明内脏痛觉过敏与结肠上皮细胞紧密连接的表达减少有关，连接蛋白和增加的细胞旁通透性。我们的实验室和其他人报告说，表观遗传机制在慢性应激内脏伤害性神经通路中的重要作用痛觉过敏目前尚不清楚表观遗传机制是否直接参与了表达减少肠上皮紧密连接蛋白，增加细胞旁通透性和内脏痛觉过敏。在这个提议，我们提供了令人信服的初步数据支持新的假设，甲基化的抑制性组蛋白H3 K9在慢性应激和促炎性多巴胺介导的内脏炎症中起着关键作用。通过结肠上皮紧密连接蛋白的下调和细胞旁神经元的增加使用两种经验证的大鼠模型（雄性和雌性）和易患结肠炎的IBS患者（雄性）和雌性）、分化的人Caco-2细胞、人源性结肠样细胞和人源性结肠上皮样细胞细胞单层。我们将研究以下纵向一体化的具体目标，以确认 H3 K9 me 2/me 3在慢性应激相关内脏痛觉过敏的病理生理学中的作用：具体目标1：试验抑制性组蛋白H3 K9的甲基化在慢性应激中起关键作用的全球假说- 使用两种经验证的雄性动物模型诱导肠屏障功能障碍和内脏痛觉过敏; 具体目标2：研究H3 K9甲基化如何调节肠上皮细胞紧密连接基因转录以及蛋白质表达、细胞旁通透性和内脏痛觉过敏对慢性应激的反应，具体目标3：评估动物的可平移性研究人类和潜在的差异基于生物性别。该应用程序具有非常重要的意义由于慢性应激对增强内脏疼痛的临床重要性和新的整体假说，创新，因为使用了最先进的方法，以系统的方式研究全球假设和高影响力，因为有可能影响该领域的当前思维。