Estrogenic Modulation of Genitourinary Epithelial-Probiotic Cross-Talk

描述（由申请人提供）：泌尿生殖系统感染影响全世界的儿童和成人。肠道来源的或性传播的或垂直传播的病原体通过阴道传播，感染女性的泌尿生殖系统。然而，共生乳杆菌生物膜可能通过调节参与自然杀伤T （NKT）细胞活性的基因，如干扰素γ (IFNG)受体1和细菌脂质抗原呈递分子CD1d，激活泌尿生殖系统上皮细胞的抗致病性反应。反过来，阴道乳杆菌生物膜的形成可能依赖于雌激素诱导的上皮糖原的产生，糖原是共生菌衍生益生菌的食物来源，“活的微生物，如果给予足够的量，对宿主的健康有益”。我们假设雌激素刺激泌尿生殖上皮糖原生成促进益生菌乳杆菌生物膜的稳定性，其相互调节上皮cd1介导的、ifng相关的NKT细胞对病原体的反应。这一假设将通过以下目的进行验证：目的1，阐明雌激素诱导的糖原对泌尿生殖系统上皮细胞相关生物膜的影响；目的2，研究益生菌介导的NKT细胞与泌尿生殖上皮相互作用的体内和体外机制；目的3，阐明雌激素、泌尿生殖系统上皮细胞和NKT细胞相互作用在泌尿生殖系统微生物组形成中的微生态作用。通过这些研究，候选人寻求通过补充他在儿科泌尿学和适应性免疫学的研究生工作背景，并接受生物膜微生物学和先天免疫学的培训，成为一名医师调查员。在候选人职业生涯的早期，候选人将通过资助研讨会建立他作为一名内科科学家的基础；在生物膜生物学、先天免疫和儿科泌尿学方面有专家指导；科学合作;实践经验;以及侧重于生物膜、先天免疫和泌尿生殖系统生物学的教学课程。总之，这个项目将为一个成功的独立研究者的职业生涯奠定基础，并将导致雌激素和益生菌保护女性生殖泌尿道免受感染的新途径的鉴定。

DESCRIPTION (provided by applicant): Genitourinary infections affect children and adults worldwide. Gut-derived or sexually or vertically transmitted pathogens travel through the vagina to infect the female genitourinary tract. However, commensal Lactobacillus biofilms may prime genitourinary epithelial cells for anti-pathogenic responses by regulating genes which participate in natural killer T (NKT) cell activity, such as interferon gamma (IFNG) receptor 1 and the bacterial lipid antigen-presenting molecule CD1d. In turn, the formation of vaginal Lactobacillus biofilms may depend on estrogen-induced, epithelial production of glycogen, a food source for commensal-derived probiotics, "live microorganisms which when administered in adequate amounts confer a health benefit on the host". We hypothesize that estrogen stimulation of glycogen production by genitourinary epithelium promotes stability of probiotic Lactobacillus biofilms, which reciprocally modulate epithelial CD1d-mediated, IFNG-associated NKT cell responses to pathogens. This hypothesis will be tested through the following aims: Aim 1, elucidate the effects of estrogen-induced glycogen on biofilms associated with genitourinary epithelial cells; Aim 2, investigate the in vivo and in vitro mechanisms of probiotic-mediated, NKT cell interactions with genitourinary epithelium; and Aim 3, clarify the microecologic role of estrogen, genitourinary epithelial, and NKT cell interactions in shaping the genitourinary microbiome. Through these studies, the candidate seeks to become a physician investigator by complementing his background in pediatric urology and graduate work in adaptive immunology with training in biofilm microbiology and innate immunology. During the early portion of the candidate's career, the candidate will build on his foundation as a physician scientist through grantsmanship workshops; strong mentorship by experts in biofilm biology, innate immunity, and pediatric urology; scientific collaborations; practical experience; and didactic coursework that focuses on biofilms, innate immunity, and genitourinary biology. In summary, this project will lay the groundwork for a successful career as an independent investigator and will lead to the identification of novel pathways by which estrogen and probiotics protect the female genitourinary tract from infections. PUBLIC HEALTH RELEVANCE: Biofilms of commensal vaginal bacteria may have probiotic (beneficial) properties which prime the genitourinary tract for natural killer T cell responses against infections. This proposal will examine how these biofilms grow on genitourinary epithelium, and how probiotics, estrogen, genitourinary epithelium, and natural killer T cells interact to determine which bacteria grow in the female genitourinary tract.