Aging-specific gene expression in Drosophila

果蝇中衰老特异性基因的表达

• 批准号: 9353539
• 负责人: JOHN Gerard TOWER
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353539
• 关键词: Address; Age; Aging; Alleles; Alzheimer' s Disease; Autoimmune Diseases; Autophagocytosis; Biological Models; Cardiovascular Diseases; Cell Lineage; Cell model; Cells; Data; Development; Disease; Dopamine; Dosage Compensation (Genetics); Down-Regulation; Drosophila genus; Drug Targeting; Estrogens; Failure; Female; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Health; High-Throughput Nucleotide Sequencing; Hormones; Human; Immune response; Incidence; Inflammation; Inherited; Intervention; Laboratories; Life Cycle Stages; Link; Liver; Longevity; MDM2 gene; Maintenance; Malignant Neoplasms; Mammals; Methods; Mitochondria; Mitochondrial DNA; Molecular; Molecular Chaperones; Mothers; Mutation; Nuclear; Osteoporosis; Oxidative Stress; Parkinson Disease; Partner in relationship; Pattern; Pharmaceutical Preparations; Phenotype; Pigments; Proteins; Regulation; Regulator Genes; Reporter; Reproduction; Research; Signal Transduction; Stroke; TP53 gene; Testing; Tissues; Transgenic Organisms; Variant; X Inactivation; age related; behavior test; biological adaptation to stress; chemical genetics; fly; gene induction; human disease; juvenile animal; male; mitochondrial genome; pleiotropism; pressure; response; sex; sexual dimorphism; small molecule; transcriptome; transcriptome sequencing

 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.

 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反应、氧化应激反应和蛋白毒性反应的诱导。我们将检验性别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，从而促进线粒体未折叠蛋白反应（UPRmt）、炎症和衰老。我们测试了保守基因，包括 p53、剂量补偿 (DC) 机制和多巴胺信号传导。这些方法包括荧光转基因报告构建体、线粒体基因组和细胞转录组的高通量测序、果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延长寿命和减少炎症的能力。 AIM 1 研究繁殖和寿命之间的权衡机制，包括 DC 机制、p53 和小分子。 AIM 2 解决了卵细胞（类肝细胞）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人类致病线粒体异质性和突变的模型系统。 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，这项研究可能会确定衰老过程中线粒体维持失败的机制（部分）在人类中保守，并且可能会确定有希望的遗传目标和药物，用于针对人类炎症和衰老相关疾病的性别特异性干预。