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: 10371024
• 负责人: Charles Robert Wira
• 金额: $ 47.19万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371024
• 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; Epithelial Cells; Escherichia coli; 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 of activation protein; 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; Woman; adaptive immune response; adaptive immunity; age group; age related; aged; antimicrobial; base; 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; recruit; reproductive; reproductive tract; response

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中粘膜免疫的影响 鉴于感染的风险增加，缺乏免疫知识，绝经后妇女的（FRT） 随着妇女的年龄而发生的变化。认识到更年期和伴随性交 激素从根本上改变了FRT的免疫环境，该提议的总体目标是到达 通过对衰老（50-59、60-69和> 70yr）如何影响病原体识别的机械理解，免疫 上和下FRT中免疫反应的保护和诱导。该提案有3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 上皮细胞是针对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）信号被衰老损害。我们还将确定年龄 具有抗菌和趋化能力的分泌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衰老对局部免疫保护的影响 整个FRT的T细胞功能。在此目标中，我们将评估细胞毒性活性的年龄依赖性变化 在激活CD4+和CD8+组织后，分泌的免疫反应（抗菌和细胞因子） 整个FRT的居民和非居民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。该目标将确定与DCS和 DC诱导T细胞反应的能力以及控制DC作为女性年龄的机制。 这项研究的独特之处在于它与我们对先天和适应性粘膜免疫的理解相结合 整个人类FRT的系统直接与最有可能的细胞粘膜保护有关 互动并应对病原体。这些研究将提供急需的信息，这对于 确定FRT中免疫功能的年龄相关的变化并影响对尿路感染的反应 （UTI）和性传播感染（STIS）。由于通常将老年妇女排除在预防之外 关于性传播感染和疫苗接种建议（例如HPV）的研究，我们的研究将为 定义老年妇女的粘膜免疫保护，并制定适当的策略以预防 新的感染和病原体重新激活。