Impact of Aging on Mucosal Immune Protection in the Female Reproductive

项目总结/摘要 迫切需要了解衰老对女性生殖道粘膜免疫的影响 (FRT)绝经后妇女，由于感染的风险增加和缺乏免疫知识， 随着女性年龄的增长而发生的变化。认识到更年期和随之而来的性生活缺失 激素从根本上改变了FRT中的免疫环境，这项建议的总体目标是达到 在对衰老（50-59岁，60-69岁和> 70岁）如何影响病原体识别的机制理解中，免疫 在上FRT和下FRT中保护和诱导免疫应答。该提案有三个原始目标： 1)确定衰老损害FRT上皮细胞免疫保护的程度。作为 上皮细胞是抵御病原体的第一道防线，我们将确定在何种程度上模式 上皮细胞的识别受体（PRR）信号传导随着老化而受损。我们还要确定年龄- 分泌的具有抗菌和趋化能力的固有分子的依赖性变化。 2)通过评估居民和非居民来确定衰老对局部免疫保护的影响 整个FRT的T细胞功能。在这个目标中，我们将评估细胞毒活性的年龄依赖性变化 以及在CD 4+和CD 8+组织活化后分泌的免疫应答（抗菌剂和细胞因子） 常驻和非常驻T细胞在整个FRT。 3)确定衰老对树突状细胞（DC）识别病原体和诱导T细胞的影响 整个FRT的响应。这一目标将确定与年龄相关的变化，在PRR反应的DC和 DC诱导T细胞反应的能力，以及随着女性年龄增长控制DC功能的机制。 这项研究的独特之处在于它将衰老与我们对先天和适应性粘膜免疫的理解结合起来， 系统，因为它直接涉及粘膜保护的细胞最有可能 相互作用并对病原体作出反应。这些研究将提供急需的信息， 确定FRT中免疫功能的年龄相关变化，并影响对尿路感染的反应 性传播感染（STIs）。由于老年妇女一般被排除在预防之外， 性传播感染的研究和疫苗接种建议（例如HPV），我们的研究将为以下方面提供基础： 确定老年妇女的粘膜免疫保护，并制定适当的预防策略， 新的感染和病原体复活。

Project Summary/Abstract An urgent need exists to understand the impact of aging on mucosal immunity in the female reproductive tract (FRT) of postmenopausal women, given the increased risk of infections and the lack of knowledge of immune alterations that occur as women age. Recognizing that menopause and the accompanying absence of sex hormones fundamentally alters the immune environment in the FRT, the overall goal of this proposal is to arrive at a mechanistic understanding of how aging (50-59, 60-69 and >70yrs) impacts pathogen recognition, immune protection and induction of immune responses in the upper and lower FRT. This proposal has 3 original Aims: 1) Determine the extent to which aging compromises immune protection by FRT epithelial cells. As epithelial cells are the first line of defense against pathogens, we will identify the extent to which pattern recognition receptor (PRR) signaling by epithelial cells is compromised with aging. We will also determine age- dependent changes in secreted innate molecules with antimicrobial and chemotaxis capacity. 2) Determine the impact of aging on local immune protection by evaluating resident and non-resident T cell function throughout the FRT. In this Aim, we will evaluate age-dependent changes in cytotoxic activity and secreted immune responses (antimicrobials and cytokines) following activation of CD4+ and CD8+ tissue resident and non-resident T cells throughout the FRT. 3) Determine the impact of aging on dendritic cell (DC) pathogen recognition and induction of T cell responses throughout the FRT. This aim will identify age-associated changes in PRR responses by DCs and in DC's ability to induce T cell responses, as well as the mechanisms that control DC function as women age. This study is unique in that it integrates aging with our understanding of the innate and adaptive mucosal immune system throughout the human FRT, as it relates directly to mucosal protection by the very cells most likely to interact and respond to pathogens. These studies will provide much needed information that is essential to identify age-related changes in immune function in the FRT and influence responses to urinary tract infections (UTIs) and sexually-transmitted infections (STIs). As older women are generally excluded from prevention research for STIs, and vaccination recommendations (for example HPV), our studies will provide a foundation to define mucosal immune protection in elderly women and develop appropriate strategies for the prevention of new infections and pathogen reactivation.