GENETIC ANALYSIS OF IMMUNOSENECENCE

免疫衰老是人们对老年人免疫反应的一种知之甚少的现象。在老年人(和小鼠)中，这种免疫紊乱的特点是创伤或感染后预后较差，对实验引入的免疫刺激反应较弱，但许多促炎细胞因子水平升高。我们发现，果蝇也表现出类似的免疫衰老。特别是，老年果蝇的抗菌肽水平较高，但对免疫挑战的反应较差。控制致炎细胞因子和抗菌肽产生的天然免疫识别和信号系统在昆虫和哺乳动物之间高度保守。因此，对苍蝇免疫衰老的详细研究将导致对人类类似过程的新见解。我们假设，老化的文件具有弱的免疫反应，这导致持续感染和抗菌肽水平上升。我们将在目标1中直接研究这一点。我们进一步提出了两种可能的机制，即通过衰老来调节免疫反应。 在目标2中，我们将从分子细节上研究胰岛素/胰岛素样信号直接影响免疫的可能性，胰岛素/胰岛素样信号被认为是寿命的关键调节器。在目标3中，我们将扩大这一方法，并使用Fona/ard基因筛查来确定影响先天免疫功能障碍随年龄发展的新途径。

Immune senescence is a pooriy understood phenomenon characteristic of the immune response of the aged. In aged humans (and mice), this immune disregulafion is characterized by poor a prognosis following traumatic injury or infection, a weak response to experimentally introduced immune sfimulafion, but an elevated level of many pro-inflammatory cytokines. We have found that Drosophila melanogaster also exhibits a similar immune senescence. In particular, aged flies have elevated levels of anfimicrobial pepfides but respond pooriy to immune challenge. The innate immune recognition and signaling systems that control pro-inflammatory cytokine and antimicrobial peptide production are highly conserved between insects and mammals. Therefore, the detailed examinafion of immune senescence in flies will lead to new insights into similar processes in humans. We hypothesize that aged files have a weakened immune response, which leads to persistent infections and elevated levels of antimicrobial peptides. This will be directly examined in Aim 1. We further propose two possible mechanisms by which the immune response is modulated by aging. In Aim 2, we will investigate in molecular detail the possibility that the Insulin/ Insulin like Signaling, which is known to be a critical modulator of lifespan, directly affect immunity. In Aim 3, we will broaden this approach and use a fonA/ard genetic screen to identify novel pathways affecting the progression of innate immune dysfunction with age.