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.

项目概要/摘要 迫切需要了解衰老对女性生殖道粘膜免疫的影响 (FRT) 绝经后妇女的感染风险增加以及缺乏免疫知识 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 FRT 中的免疫环境，该提案的总体目标是 从机械角度理解衰老（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 的免疫反应。该提案有 3 个最初目标： 1) 确定衰老对 FRT 上皮细胞免疫保护的影响程度。作为 上皮细胞是抵御病原体的第一道防线，我们将确定模式的程度 上皮细胞的识别受体（PRR）信号传导会随着衰老而受到损害。我们还将确定年龄- 具有抗菌和趋化能力的分泌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 细胞在整个 FRT 期间发挥功能。在这个目标中，我们将评估细胞毒性活性的年龄依赖性变化 CD4+ 和 CD8+ 组织激活后分泌的免疫反应（抗菌剂和细胞因子） 整个 FRT 中的驻留和非驻留 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 整个 FRT 的响应。该目标将确定 DC 和 PRR 反应中与年龄相关的变化 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性和适应性粘膜免疫的理解结合起来 整个人类 FRT 系统，因为它与最有可能的细胞的粘膜保护直接相关 与病原体相互作用并做出反应。这些研究将提供急需的信息，这些信息对于 识别 FRT 中免疫功能与年龄相关的变化并影响对尿路感染的反应 （尿路感染）和性传播感染（STI）。由于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），我们的研究将为 定义老年妇女的粘膜免疫保护并制定适当的预防策略 新的感染和病原体重新激活。