STDs, Cytokines, and Hormonal Contraception

描述（由申请人提供）：候选人：Dr. Ghanem，M.D.，是传染病的助理教授，约翰霍普金斯大学医学院临床研究研究生培训项目的候选人。这个K23重新提交的目标是通过重点教学和导师和合作者的综合专业知识来提高他的实践研究技能和实验室技能。这些技能将补充他迄今为止在培训中获得的理论技能，使他成为一名独立和富有成效的翻译研究人员。 背景：全世界有超过1亿妇女使用激素避孕药（HC）。它们对粘膜和全身免疫反应的影响知之甚少。观察性研究已将HC使用与包括HIV在内的性传播感染（STI）风险增加联系起来。初步数据：我们已经表明，在人源性宫颈和阴道上皮细胞培养模型中细胞因子的产生受到性激素的影响。这一发现扩展到967名妇女的纵向研究，其中孕激素为基础的HC被发现是下生殖道炎症的独立预测因子。 具体目标：1）比较宫颈阴道灌洗液与宫颈内、宫颈外和阴道吸液芯在评估下生殖道粘膜免疫应答方面的作用; 2）确定HC的使用是否影响淋病奈瑟菌感染妇女治疗前后宫颈阴道可溶性和细胞炎症标志物的水平;和3）确定HC的使用是否影响针对N.淋病外膜蛋白。 重要性：该提案的发现将有助于确定测量生殖器免疫反应的最佳方法;它们将提供可能指导专门针对HC使用者的STI筛查策略的引入的数据，并且它们将有助于确定性激素作为女性粘膜疫苗佐剂的潜在作用。

DESCRIPTION (provided by applicant): Candidate: Dr. Ghanem, M.D., is an Assistant Professor of Infectious Diseases and a Ph.D. candidate in the Graduate Training Program in Clinical Investigation at Johns Hopkins University School of Medicine. The goal of this K23 resubmission is to enhance his practical research skills and laboratory-based skills through focused didactics and the combined expertise of mentors and collaborators. These skills will complement the theoretical skills he has acquired thus far in his training, allowing him to become an independent and productive translational researcher. Background: Over 100 million women worldwide use hormonal contraceptives (HC). Their effects on mucosal and systemic immune responses are poorly understood. Observational studies have linked HC use to increased risk of sexually transmitted infection (STI) acquisition, including HIV. Preliminary Data: We have shown that cytokine production in a human-derived cervical and vaginal epithelial cell culture model was influenced by sex hormones in a compartment-specific manner. This finding was extended to a longitudinal study of 967 women where progesterone based HC were found to be independent predictors of lower genital tract inflammation. Specific Aims: 1) To compare cervicovaginal lavage fluid to endocervical, ectocervical, and vaginal wicks in evaluating lower genital tract mucosal immune responses; 2) To determine whether the use of HC affects cervicovaginal levels of soluble and cellular markers of inflammation in women infected with Neisseria gonorrhoeae, before and after therapy; and 3) To determine whether the use of HC affects systemic humoral and T-cell responses directed against N. gonorrhoeae outer membrane proteins. Significance: The findings from this proposal will help define optimal methods to measure genital immune responses; they will provide data that may guide the introduction of STI screening strategies specifically targeting HC users, and they will help define the potential role of sex hormones as adjuvants for mucosal vaccines in women.