Impact of Aging on Mucosal Immune Protection in the Female Reproductive

衰老对女性生殖粘膜免疫保护的影响

• 批准号: 10547801
• 负责人: Charles Robert Wira
• 金额: $ 46.56万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547801
• 关键词: Accounting; Address; Affect; Age; Aging; Anti-Bacterial Agents; Antigen-Presenting Cells; Biological Assay; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cervix Uteri; Chemotaxis; Chlamydia trachomatis; Clinical Trials; Defense Mechanisms; Dendritic Cells; Developed Countries; Development; Elderly; Elderly woman; Endometrium; Environment; Epithelial Cells; Epithelium; Escherichia coli; Exclusion; Exocervix; Face; Female; Foundations; Genitourinary System Infection; Goals; Gonadal Steroid Hormones; Health; Helper-Inducer T-Lymphocyte; Human; Human Papillomavirus; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Innate Immune System; Knowledge; Ligands; Mediating; Mediator; Menopause; Morbidity - disease rate; Mucosal Immune System; Mucosal Immunity; Mucous Membrane; Natural Immunity; Neisseria gonorrhoeae; Pathway interactions; Pattern recognition receptor; Population; Postmenopause; Predisposition; Premenopause; Prevention Research; Prevention strategy; Public Health; Receptor Signaling; Recommendation; Reproductive Tract Infections; Risk Factors; Sex Behavior; Sexually Transmitted Diseases; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Urinary tract; Urinary tract infection; Uterus; Vaccination; Vaccines; Viral; Woman; adaptive immune response; adaptive immunity; age group; age related; aged; antimicrobial; cytokine; cytotoxic; cytotoxic CD8 T cells; epidemiology study; first responder; human female; human old age (65+); immune function; improved; infection rate; infection risk; innate immune function; interest; mortality; older women; pathogen; permissiveness; recruit; reproductive; reproductive tract; response; transmission process

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.

项目摘要/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，鉴于感染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，这项提议的总体目标是 对衰老(50-59岁、60-69岁和70岁)如何影响病原体识别、免疫 保护和诱导上、下FRT中的免疫反应。这项提议最初有三个目标： 1)确定衰老对FRT上皮细胞免疫保护的影响程度。AS 上皮细胞是抵御病原体的第一道防线，我们将在多大程度上识别这种模式 上皮细胞的识别受体(PRR)信号随着年龄的增长而受损。我们还将确定年龄- 分泌的具有抗菌和趋化能力的先天分子的依赖性变化。 2)通过评估居民和非居民来确定老龄化对局部免疫保护的影响 T细胞在FRT的整个过程中发挥作用。在这个目标中，我们将评估细胞毒活性随年龄的变化。 以及在激活CD4+和CD8+组织后分泌的免疫反应(抗菌素和细胞因子) FRT中的常驻和非常驻T细胞。 3)确定衰老对树突状细胞(DC)病原体识别和T细胞诱导的影响 在整个FRT过程中都有反应。这一目标将确定DC在PRR反应中的年龄相关变化，并 DC诱导T细胞反应的能力，以及控制DC功能的机制随着女性年龄的增长而变化。 这项研究的独特之处在于，它将衰老与我们对天然和适应性粘膜免疫的理解结合在一起。 整个人类FRT系统，因为它直接与粘膜保护有关，正是这种细胞最有可能 相互作用并对病原体做出反应。这些研究将提供急需的信息，这些信息对于 确定FRT中与年龄相关的免疫功能变化，并影响对尿路感染的反应 (性传播感染)和性传播感染(性传播感染)。因为老年妇女通常被排除在预防之外 性传播感染的研究和疫苗接种建议(例如HPV)，我们的研究将提供基础 明确老年妇女的黏膜免疫保护，并制定适当的预防策略 新的感染和病原体重新激活。