Modulation of Colonic Epithelial Permeability by Sex Hormones

描述（由申请人提供）：女性主要受肠易激综合征（IBS）的影响。这种流行的原因尚未确定。有证据支持结肠中存在性别依赖性免疫激活，在内脏敏感性和上皮功能的改变中起作用。在患有IBS的女性中，激活的肥大细胞数量比患有IBS的男性多。尽管如此，肠易激综合征患者腹痛和便秘症状与结肠黏膜神经免疫功能改变的性别差异的可能性尚未被调查。基于暴露于反复应激的大鼠的初步数据，显示出内脏疼痛和上皮功能的性别特异性改变，本研究的总体目标是确定性激素对应激诱导的感觉和上皮功能改变的影响，并确定性激素在基础和应激条件下调节结肠上皮生理和随后内脏疼痛反应的机制。提出的研究旨在更好地了解内脏疼痛表达的性别差异与胃肠道上皮功能改变的关系。研究结果对转化研究和性别特异性治疗的发展具有重要意义，从而改善肠易激综合征患者的医疗保健。该候选人长期对性别相关的生物学差异感兴趣，她目前的研究主要集中在IBS啮齿动物模型中内脏疼痛调节的外周通路改变。候选人的长期目标包括成为上皮生理学研究领域的佼佼者。职业发展计划将侧重于通过教学和指导培训，培养对与内脏疼痛和便秘有关的性生物学和上皮生理学的广泛而深入的理解。候选人将由加州大学洛杉矶分校神经生物学教授Paul Micevych博士指导，他是性类固醇领域的专家，特别是在雌激素对疼痛的深刻影响的细胞和分子事件方面。此外，候选人在加州大学洛杉矶分校和加州大学圣地亚哥分校的教师中有共同导师，他们在性染色体和激素差异和疼痛（Art Arnold博士），肠上皮生理学（Kim Barrett博士），肠易激综合征神经内分泌和外周临床研究（Lin Chang博士）以及压力和神经胃肠病学（Yvette Tachi博士）方面具有专业知识。该建议的中心假设是，女性对内脏疼痛和便秘的高易感性与性激素相关的免疫（肥大细胞）和上皮（离子通道和分泌，紧密连接和渗透性）系统的性别特异性改变有关。该假设将在以下具体目标中进行检验。在Aim 1中，我们将剖析性激素和性染色体补体在应激诱导的内脏痛觉过敏的性别差异中的作用，并研究性激素对结肠粘膜肥大细胞募集和活性的影响。在目的2中，我们将通过评估卵巢激素对上皮细胞的调节作用，通过紧密连接蛋白调节/通透性、离子通道/分泌、肥大细胞释放乳糜酶和随后血管紧张素II的增加导致离子分泌减少，来解剖性染色体和性腺激素对雌性大鼠性别特异性应激诱导的结肠上皮通透性/分泌改变的影响。总之，拟议的研究将增强对性别和影响IBS疼痛敏感性和分泌的神经免疫粘膜功能之间存在的相互作用的认识，并使候选人能够提出关于IBS疼痛和便秘机制的新的可测试假设，特别是基于病理生理和性别差异的差异治疗方法

DESCRIPTION (provided by applicant): Women are predominantly affected by irritable bowel syndrome (IBS). The reason for this prevalence is not yet established. Evidence supports the presence of sex-dependent immune activation in the colon that plays role in alterations of visceral sensitivity and epithelial functions. In women with IBS, a higher number of activated mast cells are present than in men with IBS. Despite these, the possibility of sex differences in the alterations of colonic mucosal neuroimmune functions in relation with abdominal pain and constipation symptoms in IBS patients has not been investigated. Based on preliminary data in rats exposed to repeated stress showing sex-specific alterations of visceral pain and epithelial functions, the overall goal of this proposal is to establish the influence of sex hormones on stress-induced alterations of sensory and epithelial functions and determine the mechanisms by which sex hormones both under basal and stress conditions modulate colonic epithelial physiology and subsequently visceral pain responses. The proposed studies intend to provide a better understanding of sex differences in the expression of visceral pain in relationship with alterations of the gastrointestinal epithelial function. The findings should have significant implications for translational research and the development of sex- specific treatments, thereby improving health care for IBS patients. The candidate has a long-standing interest in sex-related biological differences and her current research has focused on altered peripheral pathways in the modulation of visceral pain in rodent models of IBS. The candidate's long term goals include becoming established in the field of epithelial physiology research. The career development plan will focus on developing a broad-based and in depth understanding of sex biology and epithelial physiology as they relate to visceral pain and constipation through didactic and mentored training. The candidate will be mentored by Dr. Paul Micevych, Professor in the Department of Neurobiology at UCLA and expert in the sex steroids field, in particular in the cellular and molecular events underlying estrogen's profound effects on pain. In addition, the candidate has co- mentors at UCLA and UCSD faculty members with expertise in sex chromosome and hormone differences and pain (Dr. Art Arnold), intestinal epithelial physiology (Dr. Kim Barrett), IBS neuroendocrine and peripheral clinical studies (Dr. Lin Chang) and stress and neurogastroenterology (Dr. Yvette Tachi). The central hypothesis of this proposal is that the higher susceptibility of females to visceral pain and constipation is related to sex-specific alterations of the immune (mast cells) and epithelial (ion channels and secretion, tight junctions and permeability) systems related to sex hormones. The hypothesis will be tested in the following specific aims. In Aim 1, we will dissect the role of gonadal hormones and sex chromosome complements in the sex difference in stress-induced visceral hyperalgesia and examine the influence of gonadal hormones on the recruitment and activity of colonic mucosal mast cells. In Aim 2, we will dissect the influence of sex chromosome and gonadal hormones on the sex- specific stress-induced alterations colonic epithelial permeability/secretion in female rats by assessing the modulatory effect of ovarian hormones on epithelial cells via tight junctions proteins modulation/permeability and on ion channels/secretion and on mast cells release of chymase and subsequent increase in angiotensin II leading to a reduction in ion secretion. Together, the proposed studies will enhance knowledge on interactions existing between sex and neuroimmune mucosal functions influencing pain sensitivity and secretion in IBS and enable the candidate to propose new testable hypotheses regarding mechanisms of IBS pain and constipation, in particular regarding differential treatment approaches based on pathophysiology and sex differences PUBLIC HEALTH RELEVANCE: The long term goal of this proposal is to improve treatment strategies for patients with irritable bowel syndrome (IBS), by providing a better understanding of sex differences and the influence of sex hormones in neuroimmune epithelial dysfunctions and associated alterations of visceral pain and secretion contributing to IBS pathophysiology.