The affect of hormones and oxygen-limitation on gonococcal pathophysiology

激素和限氧对淋球菌病理生理学的影响

• 批准号: 7903399
• 负责人: Jennifer L Edwards
• 金额: $ 31.49万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903399
• 关键词: Address; Adherence; Affect; Area; Bacteria; Bacterial Infections; Binding Proteins; Biochemical; Biological Models; C3bi; Cell Line; Cell model; Cell-Free System; Cells; Cervical; Cervicitis; Chronic; Chronic Disease; Clinical Data; Complement; Complement Receptor; Data; Detection; Development; Disease; Employee Strikes; Environment; Epithelial; Epithelial Cells; Epithelium; Estradiol; Exhibits; Female; Functional disorder; Future; Gender; General Population; Genital system; Genitourinary system; Goals; Gonococcal Pilus; Gonorrhea; Health; Health Care Costs; Hormonal; Hormones; Human; Hypoxia; Infection; Inflammatory; Investigation; Knowledge; Laboratories; Ligands; Male urethral structure; Malignant - descriptor; Mammalian Cell; Mediating; Menstruation; Methods; Mission; Modeling; Molecular; Molecular Profiling; Mus; Neisseria gonorrhoeae; Neonatal; Oxygen; Pathogenesis; Patients; Physiological; Play; Prevalence; Process; Production; Progesterone; Research; Role; Site; Specificity; Stress; Techniques; Testing; Therapeutic; Translating; Woman; Women' s Health; Work; base; combat; human disease; human male; improved; in vivo; innovation; insight; men; porin; protein expression; public health relevance; receptor; reproductive; response; steroid hormone; steroid hormone receptor; therapeutic development

DESCRIPTION (provided by applicant): Clinical data indicate that there is a hormonal component to gonococcal infection in women; however, the effect of steroid hormones and oxygen limitation to gonococcal infection is an under-investigated, important, area of study. Our long-term goal is to elucidate the dynamic interactions, occurring between the gonococcus and the cervical epithelium, which contribute to asymptomatic disease in women, with the ultimate goal of improved women's health. The intent of this application is to provide a detailed understanding of how gonococci respond to steroid hormones, as well as to oxygen limitation (hypoxia), as would occur, in vivo, within the cervical microenvironment during gonococcal infection. It is our central hypothesis that, in vivo, gonococcal cervicitis is governed by oxygen limitation as well as by hormone-induced changes to the gonococcus and to the cervical epithelium. Asymptomatic cervicitis is the primary factor contributing to the propensity of women to develop chronic gonococcal disease sequelae, which translates into substantial associated health cost. Therefore, the rationale for the proposed studies is that a greater understanding of gonococcal pathogenesis in the context of the menses cycle is imperative to the future development of therapeutic strategies to combat gonococcal disease and to provide the framework for improved women's health. Thus, the proposed research is directly applicable to that part of the NIH's mission that pertains to the development of fundamental knowledge that will reduce the burden of human illness. Guided by strong preliminary data, two specific aims will be pursued to test this hypothesis: 1) Define changes occurring during cervical infection in the N. gonorrhoeae expression profile in response to steroid hormones and oxygen limitation; and 2) Define the effect of steroid hormones and oxygen limitation on the complement-gonococcus interaction in a primary human cervical epithelial cell model. Within Aim 1, we will identify gonococal constituents that are likely to contribute to gonococcal disease in vivo. A subset of these molecules will be analyzed further to define their potential contribution to promoting cervical disease. Complement production is responsive to steroid hormones and plays a critical role in mediating cervical infection. Thereby, Aim 2 comprises analyses to further define the complement-gonococcus interaction under conditions likely to be encountered in vivo. We will also characterize a putative gonococcal complement binding protein, NGO0033. A variety of cellular, molecular, and biochemical techniques will be used to complete the objectives of our Specific Aims. These investigations are the first to examine how combined, variable, physiological levels of steroid hormones and hypoxia potentially modulate bacterial pathogenesis by using a primary, human, epithelial cell model, and, thus, are innovative. The proposed research is significant because it is expected to generate exceedingly meaningful data regarding how gonococci respond to exogenous stresses (i. e. hormones, complement, and/or oxygen limitation) in the context of mucosal epithelial infection. PUBLIC HEALTH RELEVANCE: Women are more prone to develop chronic, often severe, consequences as a result of cervical infection with Neisseria gonorrhoeae, the bacterium that causes gonorrhea. The focus of this application is to define the effect of steroid hormones and oxygen limitation to gonococcal disease. The proposed studies are an important and under-investigated area of bacterial pathogenesis and are applicable to human health.

描述（申请人提供）：临床数据表明，女性淋球菌感染与激素成分有关；然而，类固醇激素和氧气限制对淋球菌感染的影响是一个尚未充分调查的重要研究领域。我们的长期目标是阐明淋球菌和宫颈上皮之间发生的动态相互作用，这种相互作用导致女性无症状疾病，最终目标是改善女性健康。该应用的目的是详细了解淋球菌如何对类固醇激素以及淋球菌感染期间宫颈微环境中体内发生的氧限制（缺氧）做出反应。我们的中心假设是，在体内，淋球菌性宫颈炎受氧限制以及激素诱导的淋球菌和宫颈上皮变化的控制。无症状宫颈炎是导致妇女罹患慢性淋球菌病后遗症的主要因素，这会带来巨大的相关健康成本。因此，拟议研究的基本原理是，更好地了解月经周期背景下的淋球菌发病机制对于未来制定对抗淋球菌疾病的治疗策略并为改善妇女健康提供框架至关重要。因此，拟议的研究直接适用于 NIH 使命的一部分，即与发展基础知识以减轻人类疾病负担有关的部分。在强有力的初步数据的指导下，将追求两个具体目标来检验这一假设：1）定义宫颈感染期间淋病奈瑟菌表达谱对类固醇激素和氧气限制的反应发生的变化； 2) 确定类固醇激素和氧限制对原代人宫颈上皮细胞模型中补体-淋球菌相互作用的影响。在目标 1 中，我们将确定可能导致体内淋球菌疾病的淋球菌成分。这些分子的一个子集将被进一步分析，以确定它们对促进宫颈疾病的潜在贡献。补体的产生对类固醇激素有反应，在介导宫颈感染中发挥着关键作用。因此，目标 2 包括进一步确定体内可能遇到的条件下补体-淋球菌相互作用的分析。我们还将表征一种假定的淋球菌补体结合蛋白 NGO0033。将使用各种细胞、分子和生化技术来完成我们的具体目标。这些研究首次通过使用原代人类上皮细胞模型来研究类固醇激素和缺氧的组合、可变生理水平如何潜在地调节细菌发病机制，因此具有创新性。拟议的研究意义重大，因为预计它将产生关于淋球菌如何在粘膜上皮感染的情况下对外源性应激（即激素、补体和/或氧限制）做出反应的极其有意义的数据。公共卫生相关性：女性更容易因宫颈感染淋病奈瑟菌（引起淋病的细菌）而出现慢性且通常严重的后果。该应用的重点是确定类固醇激素和氧气限制对淋球菌疾病的影响。拟议的研究是细菌发病机制的一个重要且尚未得到充分研究的领域，适用于人类健康。