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，这种激活在内脏敏感性和上皮功能的改变中发挥作用。在患有IBS的女性中，激活的肥大细胞的数量比患有IBS的男性更多。尽管如此，IBS患者结肠粘膜神经免疫功能改变与腹痛和便秘症状相关的性别差异的可能性尚未被调查。基于反复应激大鼠的初步数据显示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，并确定基础和应激条件下性激素调节结肠上皮生理和随后内脏疼痛反应的机制。建议的研究旨在更好地了解内脏疼痛表达的性别差异与胃肠上皮功能改变的关系。这一发现将对转化性研究和针对性别的治疗方法的开发具有重要意义，从而改善IBS患者的医疗保健。这位候选人长期以来一直对与性别相关的生物学差异感兴趣，她目前的研究重点是在IBS啮齿动物模型中调节内脏疼痛的外周通路的改变。应聘者的长期目标包括在上皮生理学研究领域站稳脚跟。职业发展计划的重点将是通过授课和辅导培训，对与内脏疼痛和便秘有关的性生物学和上皮生理学进行广泛和深入的了解。候选人将由加州大学洛杉矶分校神经生物学系教授保罗·米切维奇博士指导，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背后的细胞和分子事件方面。此外，候选人还在加州大学洛杉矶分校和加州大学圣迭戈分校的教职员工中担任共同导师，他们在性染色体、激素差异和疼痛(Art Arnold博士)、肠上皮生理学(Kim Barrett博士)、IBS神经内分泌和外周临床研究(林畅博士)以及压力和神经胃肠病(Yvette Tachi博士)方面拥有专业知识。这一建议的中心假设是，女性对内脏疼痛和便秘的更高敏感性与与性激素相关的免疫(肥大细胞)和上皮(离子通道和分泌、紧密连接和通透性)系统的性别特异性变化有关。这一假设将在以下具体目标中得到检验。在目标1中，我们将剖析性腺激素和性染色体补体在应激性内脏痛觉过敏中的性别差异中的作用，并检测性腺激素对结肠粘膜肥大细胞募集和活性的影响。在目标2中，我们将通过评估卵巢激素通过紧密连接蛋白调节/通透性和对离子通道/分泌的调节作用，以及对肥大细胞释放凝乳酶和随后血管紧张素II增加导致离子分泌减少的调节作用，剖析性染色体和性腺激素对性应激诱导的雌性大鼠结肠上皮通透性/分泌改变的影响。总之，拟议的研究将加强对影响IBS疼痛敏感性和分泌物的性别和神经免疫粘膜功能之间相互作用的了解，并使候选人能够就IBS疼痛和便秘的机制提出新的可检验的假说，特别是关于基于病理生理学和性别差异的区别治疗方法。 公共卫生相关性：这项建议的长期目标是通过更好地了解性别差异和性激素在神经免疫上皮功能障碍和相关的内脏疼痛和分泌物变化中的影响，改善肠易激综合征(IBS)患者的治疗策略，从而促进IBS的病理生理。

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.