Mechanisms underlying sex differences in the pathogenesis of IBD

描述(由申请人提供)：最近有报道称炎症性肠病(IBD)的严重程度存在性别差异，女性克罗恩病(CD)患者可能比男性经历更严重的疾病表现，以及与青春期、妊娠期和产后荷尔蒙激增相关的症状活动。虽然目前确切的病因尚不清楚，但公认的是，IBD是由于遗传易感个体对环境因素(如肠道微生物区系)的免疫反应失调所致。然而，IBD性别差异背后的机制(S)是一个研究较少的领域，关于遗传、宿主免疫以及肠道微环境如何协调导致性别差异，尤其是在克罗恩病患者中，人们知之甚少。基于我们广泛的初步数据，本提案的中心假设是通过TLR9传递信号的肠道微生物配体促进了粘膜Treg种群的表型和功能多样性，这有助于实验性CD的性别差异，例如在SAMP小鼠、CD样回肠炎的自发模型和CD患者中观察到的性别差异。这一假设将通过执行两个特定的 目的：1)确定肠道微生物区系对粘膜Treg群体/亚群的表型和功能特性的性别差异的影响；2)确定TLR9激活如何特异性地导致与性别相关的肠道炎症的机制(S)。拟议的研究旨在阐明自发的实验性克罗恩样回肠炎患者性别差异的潜在机制(S)，并确定潜在的早期疾病途径，这些途径可以导致开发新的、针对性别的策略来改善这种毁灭性疾病患者的治疗。

DESCRIPTION (provided by applicant): Gender disparity has been recently reported for the severity of inflammatory bowel disease (IBD), with female patients with Crohn's disease (CD), one of the idiopathic IBDs, likely to experience more severe disease manifestations compared to males, and with symptom activity associated with hormonal surges during puberty, pregnancy and the post-partum period. Although the precise etiology is currently unknown, it is well accepted that IBD results from a dysregulated immune response to environmental factors (e.g., gut microflora) in genetically-predisposed individuals. However, the mechanism(s) underlying sex differences in IBD is an understudied area of investigation and little is known regarding how the orchestration of genetics, host immunity, as well as the gut microenvironment leads to gender disparity, specifically in Crohn's patients. Based on our extensive preliminary data, the central hypothesis of the present proposal is that gut microbial ligands signaling through TLR9 promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in experimental CD, such as that observed in SAMP mice, a spontaneous model of CD-like ileitis, and in patients with CD. This hypothesis will be tested by performing two specific aims: 1) Determine the impact of the gut microbiota on sex differences in the phenotypic and functional properties of the mucosal Treg population/subpopulations, and 2) Determine the mechanism(s) as to how TLR9 activation specifically results in sex-associated gut inflammation. The proposed studies are designed to elucidate potential mechanism(s) underlying sex differences in spontaneous, experimental Crohn's-like ileitis, and identify potential, early diseas pathways that can lead to the development of novel, gender-targeted strategies to improve treatment of patients suffering from this devastating disease.