Mechanisms of Antigen Processing and Presentation in Aging Dendritic Cells (Proje

项目摘要 初级淋巴器官的免疫衰老的特征是其自我更新能力下降 前体细胞以及受年龄相关变化影响的谱系承诺细胞的生成。这个 免疫力下降的后果是对感染和癌症的易感性增加，反应减弱。 为了接种疫苗。我们最近与该计划项目(PP)的P1和P3合作报告，a 衰老的CD34+骨髓前体细胞以及真正的传统树突状细胞(CDC)的特征是 广泛糖化、碳化和脂氧化的蛋白质组的存在，这严重损害了 它们产生有效免疫反应的能力。 在这个新的PP阶段，我们建议使用一系列的生化和生物物理方法来：1)在功能上 描述不同应激源对适应性免疫反应的影响2)分析氧化修饰 这些应激源产生的CDC和M-Φ免疫蛋白质组3)分析自噬途径 参与处理氧化修饰的蛋白质组和4)实施针对以下目标的治疗干预 减少细胞应激源，恢复适应性免疫功能。 该项目的总体工作假设是应激源诱导的翻译后特定蛋白质 修饰(羰化、糖基化、脂氧化)对细胞免疫蛋白质组有不同的影响，其 自噬清除最终发挥CDC、巨噬细胞(MΦ)和CD4+T细胞免疫功能。 在特定的目标1中，我们将分析细胞应激源对CDC和MΦ免疫蛋白质组的影响 蛋白质聚集体的定性和定量质谱学和自由流动分级分析。这个 将评估用于处理糖化、碳化和脂氧化蛋白质组的自噬机制 使用CD11c组织特异性零细胞进行三条自噬途径。 在特定的目标2中，我们将分析已知的不同应激源如何诱导蛋白毒性和脂毒性。 损害CDC介导的适应性免疫反应。 在具体目标3中，我们将评估一系列遗传、药物和饮食治疗干预措施。 与所有项目共享，以确定减少对免疫的蛋白质毒性和脂肪毒性的最佳方法 细胞和恢复适应性免疫功能 相关性：这一应用深入研究了免疫衰老和免疫细胞的未知领域。 对糖尿病、代谢综合征、长期感染和 免疫细胞衰竭。总体的基本目标是理解每一种生物化学的含义 应激源对疾控中心和M-Φ启动适应性免疫反应和制定治疗干预措施的能力 旨在恢复细胞功能和改善免疫衰老。

Project Summary Immunosenescence of primary lymphatic organs is characterized by a decrease in the self-renewing potential of precursor cells as well as generation of lineage-committed cells affected by age-related changes. The consequences of immune decline are increased susceptibility to infections and cancer, and reduced responses to vaccinations. We recently reported, in collaboration with P1 and P3 of this Program Project (PP), that a hallmark of aging CD34+ bone marrow precursor cells as well as bona fide conventional dendritic cells (cDC) is the presence of an extensively glycated, carbonylated and lipoxidated proteome, which severely compromises their ability to mount effective immune responses. In this new PP period we propose to use a series of biochemical and biophysical approaches to: 1) functionally characterize the effects of different stressors on adaptive immune responses 2) analyze oxidative modifications of the cDC and MΦ immuno-proteome generated by these stressors 3) analyze the autophagic pathways involved in disposing the oxidatively modified proteome and 4) implement therapeutical intervention aimed at decreasing cellular stressors and restore adaptive immune functions. The overall working hypothesis of this project is that stressor-induced specific protein posttranslational modifications (carbonylation, glycation, lipoxidation) differently affect the cellular immuno-proteome, its autophagic clearance and ultimately the cDC, macrophages (MΦ) and CD4+ T cell immune functions. In specific Aim 1 we will analyze the effects of cellular stressor on cDC and MΦ immunoproteome by using qualitative and quantitative mass spectrometry and free flow fractionation analysis of protein aggregates. The autophagic mechanisms use to dispose of the glycated, carbonylated and lipoxidated proteome will be evaluated using CD11c tissue specific null cells for the three autophagic pathways. In specific Aim 2 we will analyze how different stressors, known to induce proteotoxicity and lipotoxicity compromise cDC-mediated adaptive immune responses. In specific Aim 3 we will evaluate a series of genetic, pharmacologic and dietary therapeutic interventions shared with all projects to determine the best approach to decrease proteotoxicity and lipotoxicity on immune cells and restore adaptive immune functions Relevance: This application delves into previously unexplored areas of immunosenescence and immune cells response to stressors commonly encountered in diabetes, metabolic syndrome, prolonged infections and immune cell exhaustion. The overall fundamental goal is to understand the biochemical implication of each stressor on cDC and MΦ ability to mount adaptive immune responses and to devise therapeutic interventions aimed at restoring cellular functionality and improve immunosenescence.