STDs, Cytokines, and Hormonal Contraception

候选人：加尼姆博士，医学博士，传染病学助理教授，约翰霍普金斯大学医学院临床调查研究生培训计划博士生。K23重新提交的目标是通过专注的教学以及导师和合作者的综合专业知识来提高他的实际研究技能和基于实验室的技能。这些技能将补充他在培训中迄今获得的理论技能，使他成为一名独立的、多产的翻译研究人员。 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还知之甚少。观察性研究已经将HC的使用与包括艾滋病毒在内的性传播感染(STI)感染风险的增加联系在一起。初步数据：我们已经表明，在人类来源的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以一种特定的方式影响。这一发现被扩展到一项对967名女性的纵向研究，其中基于孕酮的HC被发现是下生殖道炎症的独立预测因子。 具体目的：1)比较宫颈阴道灌洗液与宫颈内、宫颈外和阴道取液在评估下生殖道黏膜免疫反应方面的差异；2)确定HC的使用是否影响淋球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；以及3)确定HC的使用是否影响针对淋球菌外膜蛋白的系统性体液和T细胞反应。 意义：这项提案的发现将有助于确定衡量生殖器免疫反应的最佳方法；它们将提供数据，指导专门针对HC使用者的STI筛查策略的引入，并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.