GENETIC ANALYSIS OF IMMUNOSENECENCE

免疫性疾病的遗传分析

• 批准号: 8377006
• 负责人: ROLF BODMER
• 金额: $ 32.56万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377006
• 关键词: Adult; Affect; Age; Aging; Animals; Autoimmune Process; Behavior; Biological Models; Cell physiology; Characteristics; Competence; Disease; Drosophila genus; Drosophila melanogaster; Exhibits; Exposure to; Family Dasypodidae; Gene Expression; Genes; Genetic Screening; Goals; Hindgut; Human; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammatory; Inflammatory Response; Injury; Insecta; Insulin; Invertebrates; Kidney; Kinetics; Lead; Liver; Longevity; Malpighian Tubules; Mammals; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Natural Immunity; Nitric Oxide; Organ Culture Techniques; Pathway interactions; Pattern; Physiological; Physiology; Play; Predisposition; Process; Production; RNA Interference; Recording of previous events; Regulation; Risk; Role; Screening procedure; Signal Pathway; Signal Transduction; Sirtuins; System; Testing; Tissues; aged; antimicrobial; antimicrobial peptide; bactericide; base; cytokine; fly; genetic analysis; genetic manipulation; immune function; immune resistance; innate immune function; insight; microbial; mortality; multicatalytic endopeptidase complex; novel; outcome forecast; pathogen; repaired; response; senescence; tool

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.

免疫衰老是一种鲜为人知的现象特征的免疫反应的老年人。在老年人类（和小鼠）中，这种免疫失调的特点是创伤性损伤或感染后预后不良，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。我们发现黑腹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升高，但对免疫挑战的反应较差。控制促炎细胞因子和抗菌肽产生的先天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，对果蝇免疫衰老的详细研究将为人类的类似过程提供新的见解。我们假设衰老的档案有一个减弱的免疫反应，这导致持续感染和抗菌肽水平升高。这将在Aim 1中直接讨论。我们进一步提出了衰老调节免疫反应的两种可能机制。