Estrogenic Modulation of Genitourinary Epithelial-Probiotic Cross-Talk

描述（由申请人提供）：泌尿生殖道感染影响全世界的儿童和成人。肠源性或性传播或垂直传播的病原体通过阴道感染女性泌尿生殖道。然而，乳酸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CD 1d）引发泌尿生殖道上皮细胞的抗病原体反应。反过来，阴道乳杆菌生物膜的形成可能取决于雌激素诱导的糖原的上皮产生，糖原是一种来自益生菌的食物来源，“当以足够的量施用时赋予宿主健康益处的活微生物”。我们推测，雌激素刺激生殖泌尿上皮细胞产生糖原，促进益生菌乳酸菌生物膜的稳定性，这间接调节上皮细胞CD 1d介导的IFNG相关的NKT细胞对病原体的反应。本研究的目的是：1、阐明雌激素诱导的糖原对泌尿生殖道上皮细胞生物膜的影响; 2、研究益生菌介导的NKT细胞与泌尿生殖道上皮细胞相互作用的体内、外机制;目的3，阐明雌激素、泌尿生殖道上皮细胞和NKT细胞相互作用在形成泌尿生殖道微生物组中的微生态作用。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研究生工作的背景，在生物膜微生物学和先天免疫学的培训，成为一名医生调查员。在候选人的职业生涯的早期部分，候选人将通过granimetry研讨会建立在他作为医生科学家的基础上;由生物膜生物学，先天免疫和儿科泌尿学专家提供强有力的指导;科学合作;实践经验;以及专注于生物膜，先天免疫和泌尿生殖生物学的教学课程。总之，该项目将为独立研究者的成功职业生涯奠定基础，并将导致识别雌激素和益生菌保护女性泌尿生殖道免受感染的新途径。 公共卫生相关性：尿道阴道细菌的生物膜可能具有益生菌（有益）特性，其引发泌尿生殖道针对感染的自然杀伤T细胞应答。该提案将研究这些生物膜如何在生殖泌尿上皮上生长，以及益生菌，雌激素，生殖泌尿上皮和自然杀伤T细胞如何相互作用，以确定哪些细菌在女性生殖泌尿道中生长。

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.