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: 8305999
• 负责人: Jennifer L Edwards
• 金额: $ 31.17万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305999
• 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; gonococcal porin; human disease; human male; improved; in vivo; innovation; insight; men; protein expression; receptor; reproductive; response; steroid hormone; steroid hormone receptor; therapeutic development; 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; gonococcal porin; human disease; human male; improved; in vivo; innovation; insight; men; protein expression; 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（由申请人提供）：临床数据表明，女性肺炎球菌感染的激素成分；然而，类固醇激素和氧气对淋球菌感染的影响是一个不受欢迎的，重要的研究领域。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，这些伴侣会导致女性无症状疾病，并最终导致女性健康的最终目标。该应用的目的是详细了解淋球菌如何应对类固醇激素以及对氧气限制（缺氧）在淋球菌感染期间的宫颈微环境中发生的情况（缺氧）。我们的中心假设是，在体内，淋球菌宫颈炎受氧限制以及激素诱导的淋巴球变化和宫颈上皮的变化控制。无症状宫颈炎是导致女性发展慢性淋球菌疾病后遗症倾向的主要因素，这转化为实质性相关的健康成本。因此，拟议的研究的理由是，在月经周期的背景下，对淋球菌发病机理的更深入了解对未来的治疗策略的发展至关重要，以打击淋球菌疾病，并为改善女性健康提供框架。因此，拟议的研究直接适用于NIH使命的那部分，该任务与基本知识的发展有关，这将减轻人类疾病的负担。在强大的初步数据的指导下，将追求两个特定的目标来检验以下假设：1）定义淋病猪笼草表达在颈椎感染期间发生的变化，以响应类固醇激素和氧气限制； 2）定义类固醇激素和氧限制对原发性人宫颈上皮细胞模型中补体造型相互作用的影响。在AIM 1中，我们将确定可能在体内导致淋球菌疾病的淋球菌成分。这些分子的一个子集将进一步分析，以定义它们对促进宫颈疾病的潜在贡献。补体产生对类固醇激素有反应，并且在介导宫颈感染中起着至关重要的作用。因此，AIM 2包括分析，以进一步定义可能在体内遇到的条件下的补体巨球菌相互作用。我们还将表征假定的淋球菌补体结合蛋白NGO0033。各种细胞，分子和生化技术将用于完成我们特定目标的目标。这些研究是第一个研究类固醇激素和缺氧的合并，可变，生理水平的方法，可能使用原代，人类的上皮细胞模型来调节细菌发病机理，从而具有创新性。拟议的研究很重要，因为预计它将在粘膜上皮感染的背景下产生有关淋球菌如何应对外源应力（即激素，补体和/或氧气限制）的非常有意义的数据。公共卫生相关性：由于宫颈淋病奈瑟氏菌（Neisseria Gonorrhoeae）的宫颈感染，妇女更容易发生慢性，通常是严重的后果，这是导致淋病的细菌。该应用的重点是定义类固醇激素和氧气对淋球菌疾病的影响。拟议的研究是细菌发病机理的重要且不足的区域，适用于人类健康。