Aging-specific gene expression in Drosophila

 描述（由申请人提供）：我们对果蝇衰老过程中基因表达变化的分析揭示了线粒体基因的下调以及先天免疫应答、氧化应激应答和蛋白毒性应答的诱导.我们将检验性分化抑制线粒体周转的假设，这与线粒体突变协同作用，导致异常线粒体的积累，促进线粒体未折叠蛋白反应（UPRmt），炎症和衰老。我们测试保守的基因，包括p53，剂量补偿（DC）机制，和多巴胺信号。这些方法包括floprotein转基因报告构建体，线粒体基因组和细胞转录组的高通量测序，苍蝇基因表达和行为的3D视频跟踪，以及测试保守基因和小分子增加寿命和减少炎症的能力。AIM 1研究生殖和寿命之间的权衡机制，包括DC机制，p53和小分子。AIM 2解决了卵母细胞（肝样细胞）中细胞特异性衰老模式的机制，包括UPRmt，MnSOD和线粒体突变。这些研究可能会产生一个模型系统的致病线粒体异质性和突变在人类。AIM 3测试了p53对寿命的性别特异性影响的可能机制，包括自噬。如果成功的话，这项研究可能会确定在衰老过程中线粒体维持失败的机制，这些机制（部分）在人类中是保守的，并且可能会确定有希望的遗传靶标和药物，用于人类炎症和衰老相关疾病的性别特异性干预。

 DESCRIPTION (provided by applicant): Our analysis of gene expression changes during Drosophila aging reveals down- regulation of mitochondrial genes and induction of innate immune response, oxidative stress response, and proteotoxicity response. We will test the hypothesis that sexual differentiation inhibits mitochondrial turnover, and this synergizes with mitochondrial mutations to cause an accumulation of abnormal mitochondria that promote the mitochondrial unfolded protein response (UPRmt), inflammation and aging. We test conserved genes including p53, the dosage compensation (DC) machinery, and dopamine signaling. The methods include florescent transgenic reporter constructs, high-throughput sequencing of mitochondrial genomes and cell transcriptomes, 3D video tracking of fly gene expression and behavior, and testing conserved genes and small molecules for ability to increase life span and reduce inflammation. AIM 1 investigates mechanisms for the trade-off between reproduction and life span, including the DC machinery, p53 and small molecules. AIM 2 addresses mechanisms for cell-specific patterns of aging in oenocytes (liver-like cells), including the UPRmt, MnSOD and mitochondrial mutations. These studies may yield a model system for disease-causing mitochondrial heteroplasmy and mutations in humans. AIM 3 tests possible mechanisms for sex-specific effects of p53 on life span, including autophagy. If successful this research may identify mechanisms for mitochondrial maintenance failure during aging that are (partly) conserved with humans, and may identify promising genetic targets and drugs for sex- specific interventions in human inflammation and aging-related disease.