Age-dependent regulation of clearance and signaling pathways

清除率和信号通路的年龄依赖性调节

• 批准号: 8088253
• 负责人: KIM D. FINLEY
• 金额: $ 29.32万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088253
• 关键词: Adult; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Autophagocytosis; Behavior; Caloric Restriction; Cell Aging; Cell physiology; Data; Data Analyses; Defect; Disease; Drosophila genus; Employee Strikes; Equilibrium; Excision; Frequencies; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Goals; Growth; Head; Homeostasis; Human; Hydrogen Peroxide; Individual; Inflammatory Response; Insulin; Insulin Receptor; Insulin Signaling Pathway; Link; Lipids; Longevity; Messenger RNA; Metabolic; Metabolic Control; Metabolic syndrome; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Muscle; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Organism; Oxidative Stress; Parkinson Disease; Pathway interactions; Pattern; Phenotype; Physiological Processes; Preparation; Prevention; Production; Property; Regulation; Research; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Sirolimus; Somatomedins; System; Techniques; Tissues; Transgenic Organisms; Ubiquitin; age related; aged; anti aging; base; biological adaptation to stress; brain tissue; cDNA Library; design; fly; gain of function; healthy aging; in vivo; longevity gene; multicatalytic endopeptidase complex; mutant; next generation; parkin gene/protein; protein aggregate; relating to nervous system; research study; response; sugar; ubiquitin-protein ligase; validation studies

DESCRIPTION (provided by applicant): As we age cellular defects accumulate and promote aging of an organism. Conserved clearance pathways, in young individuals maintain cellular homeostasis, through balancing new production with the elimination of old components. In the young there is coordinated regulation between nutritional/growth signaling pathways (i.e. Insulin and Insulin-like Growth Factor, IR/IGF) with downstream components such as autophagy and the ubiquitin-proteasome system (UPS). This balance is essential for healthy aging. Often dysregulation occurs with upstream signaling pathways leading to altered expression profiles of key clearance components. This disconnect appears in part to be the molecular underpinnings behind diseases like metabolic syndrome and type-II diabetes. These disorders are increasing in frequency, accelerate with age and are known risk factors for disorders such as Parkinson and Alzheimer's diseases. My research has focused on macroautophagy (autophagy) and its role with neuronal aging and the clearance of protein aggregates. We have found there is an age-dependent decline in autophagy gene expression and by enhancing message levels of rate-limiting genes (i.e. Atg8a) in the adult CNS we can increase aggregate clearance and the Drosophila lifespan by over 50%. We have also found that defects in the IR signaling have a profound effect on fly longevity and enhance autophagy in aging neural tissues. Other clearance pathways, such as UPS show a profound functional change with age, and are also partly under the control of metabolic signaling. The hypothesis of this proposal is that expression profiles of key components in signaling (i.e. IR, TOR) and clearance (i.e. UPS, autophagy) pathways will be altered with age. This regulatory disconnect, in turn will limit the production of factors required for the effective removal of cellular damage. Once genes are identified that have age-dependent changes to their mRNA profiles; we will use Drosophila genetic/transgenic techniques to preferentially manipulate their expression profiles to a more "youthful" pattern and individually assess their "anti-aging" properties. For Specific Aim 1 we will use Next Generation Sequencing, Microarray and qRT-PCR techniques to determine the transcriptome profiles of young and old neural and muscle tissues. In Specific Aim 2 we will use Drosophila genetic/transgenic technique to alter the expression profiles of select genes and characterize their effect on age-dependent phenotypes. Specific Aim 3 will involve characterizing transcriptome profiles from flies at different ages that have specific mutations or transgenic alterations to IR/IGF or autophagy genes. Specific Aim 4 will extend the analysis of transcriptome profiles to include samples from aged mammalian tissues. The goal of this proposal is to clarify the role that clearance pathways have in cellular aging and to identify conserved genes that could have a profound effect on human aging and neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: The cellular processes that control aging are highly conserved and share striking similarities between worms, flies and humans. By identifying which genes are critical for healthy aging and how they are regulated, we will better understanding the cellular processes that control human aging and neurodegeneration. This understanding will serve as the basis for the prevention or treatment of disorders such as type-II diabetes, metabolic syndrome and Alzheimer's disease.

描述（由申请人提供）：随着年龄的细胞缺陷，有机体的累积和促进衰老。通过平衡新的生产与消除旧组件的平衡，保守的清除途径保持了细胞稳态。在年轻人中，在营养/生长信号传导途径（即胰岛素和胰岛素样生长因子，IR/IGF）与下游组件（例如自噬和泛素蛋白蛋白 - 蛋白酶体系统（UPS））之间进行了协调调节。这种平衡对于健康衰老至关重要。通常，失调发生在上游信号通路中，导致关键清除组件的表达曲线改变。这种断开部分似乎部分是代谢综合征和II型糖尿病等疾病背后的分子基础。这些疾病的频率增加，随着年龄的增长而加速，并且是帕金森氏症和阿尔茨海默氏病等疾病的已知危险因素。我的研究集中在大型噬菌学（自噬）及其在神经元衰老和蛋白质聚集体的清除方面的作用。我们发现，自噬基因表达的年龄依赖性下降，并通过提高成人中枢神经系统中限制基因的信息水平（即ATG8A），我们可以将骨料清除率和果蝇寿命增加50％以上。我们还发现，IR信号中的缺陷对苍蝇寿命具有深远的影响，并增强了衰老神经组织的自噬。其他清除途径（例如UPS）随着年龄的增长而显示出深刻的功能变化，也部分在代谢信号传导的控制之下。该提议的假设是，信号传导（即IR，TOR）和清除（即UPS，自噬）途径中关键成分的表达谱将随着年龄的增长而改变。这种调节性断开连接，反过来将限制有效去除细胞损伤所需的因素的产生。一旦确定了与其mRNA谱的年龄变化的基因；我们将使用果蝇遗传/转基因技术优先操纵其表达谱以更“年轻”的模式，并单独评估其“抗衰老”特性。对于特定目的1，我们将使用下一代测序，微阵列和QRT-PCR技术来确定年轻和老式神经和肌肉组织的转录组谱。在特定的目标2中，我们将使用果蝇遗传/转基因技术来改变选定基因的表达谱并表征其对年龄依赖性表型的影响。特定的目标3将涉及表征来自具有特定突变或对IR/IGF或自噬基因的特异性突变或转基因改变的不同年龄的转录组曲线。具体目标4将扩展对转录组曲线的分析，以包括来自老年哺乳动物组织的样品。该提案的目的是阐明清除途径在细胞衰老中的作用，并鉴定可能对人衰老和神经退行性疾病产生深远影响的保守基因。 公共卫生相关性：控制衰老的细胞过程是高度保守的，并在蠕虫，苍蝇和人类之间具有惊人的相似性。通过识别哪些基因对于健康衰老至关重要，以及如何调节它们，我们将更好地理解控制人衰老和神经变性的细胞过程。这种理解将是预防或治疗诸如II型糖尿病，代谢综合征和阿尔茨海默氏病等疾病的基础。