Host Factors in Susceptibility to Chlamydial Disease

衣原体疾病易感性的宿主因素

• 批准号: 6708932
• 负责人: Kyle H. Ramsey
• 金额: $ 19.89万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708932
• 关键词: Chlamydia trachomatis; cellular pathology; chlamydial disease; cytokine; disease /disorder model; disease /disorder proneness /risk; elastases; enzyme activity; extracellular matrix; female reproductive system disorder; gene deletion mutation; genetically modified animals; laboratory mouse; metalloendopeptidases; tissue inhibitor of metalloproteinases; tissue mosaicism

DESCRIPTION (provided by the applicant): Chlamydia trachomatis infections are the most commonly reported transmissible diseases in the U.S. Diagnosis, treatment, and sequelae of chlamydial disease cost billions of dollars each year in the U.S. alone. The infection is often asymptomatic in women. Variations in the host immune response are likely to blame for adverse outcomes because not all persons who become infected will suffer the long-term consequences of the disease. In those who progress to disease, the affected tissues are significantly altered in their structure and function by a process that ultimately results in scarring and blockage of the fallopian tubes. This results in tubal factor infertility and risk of ectopic pregnancy. Our hypothesis is that those who sustain this outcome have dysregulation of factors which are responsible for the repair of the extracellular matrix. To address hypothesis, we will use a mouse model of chlamydial disease where inbred strains exist which have been characterized as resistant or susceptible as indicated by the outcomes of tubal damage and infertility. In approach, we will first extensively compare and contrast these strains with regard to their ability to modify and repair the extracellular matrix of the urogenital tract in vivo and in vitro. Subsequently, we will define the role of matrix metalloproteinases (MMPs) in the outcome of chlamydial disease through in vivo studies where the enzymes are inhibited pharmacologically or cytokines that influence their activity and production are neutralized. We will then define a role of specific metalloproteinases to the disease process through the use of mice with deletions in genes that encode the enzymes. Lastly, the contribution of specific inflammatory cells to the modulation of extracellular matrix in chlamydial disease will be defined by the production of bone marrow chimeras between susceptible and resistant strains of mice and subsequent depletions of leukocyte populations. In summary, it is the intent of this proposal to define host factors that are responsible for adverse chlamydial disease outcome. The information derived will assist in the development of therapies which could ameliorate the chlamydial disease process; noninvasive diagnostic indicators of progressive scarring and abnormal physiological outcome; development of prognostic indicators of those at high risk for chlamydial disease; and, further advances in design of a safe and effective chlamydial vaccine through avoidance of adverse outcomes.

描述（申请人提供）：沙眼衣原体感染是 美国诊断中最常见的可传播疾病， 治疗，衣原体疾病的后遗症每个耗资数十亿美元 仅在美国一年。女性的感染通常是无症状的。 宿主免疫反应的变化可能会导致不良后果 因为并非所有被感染的人都会长期遭受 疾病的后果。在那些发展为疾病的人中 组织的结构和功能通过一个过程显着改变 最终导致输卵管的疤痕和阻塞。这 导致输管因子不育症和异位妊娠风险。我们的 假设是那些维持这种结果的人患有失调 负责修复细胞外基质的。解决 假设，我们将使用近交的小鼠衣原体疾病模型 存在被认为是抗性或易感的菌株 由输卵管损伤和不育的结果表示。在接近方面，我们将 首先对这些菌株进行广泛比较和对比 能够修改和修复泌尿生殖道的细胞外基质 体内和体外。随后，我们将定义矩阵的作用 金属蛋白酶（MMP）通过体内在衣原体疾病的结果中 研究酶在药理学上受到抑制或细胞因子的研究 影响他们的活动和生产被中和。然后，我们将定义一个 特定金属蛋白酶在疾病过程中的作用 具有编码酶的基因中缺失的小鼠。最后，贡献 特异性炎症细胞以调节细胞外基质 衣原体疾病将由骨髓嵌合体的产生定义 在小鼠的易感和抗性菌株之间以及随后的耗竭 白细胞种群。总而言之，这是该提议定义的目的 负责不良衣原体疾病结果的宿主因素。这 得出的信息将有助于开发疗法 改善衣原体疾病过程；无创诊断指标 进行性疤痕和异常生理结果；发展 那些患衣原体疾病风险高的人的预后指标；和， 通过设计安全有效的衣原体疫苗的进一步进步 避免不利的结果。