C. Elegans as a Model of Cell Senescence and Alzheimer's Disease

项目摘要/摘要 意义：细胞衰老与许多与年龄有关的疾病有关。延缓或逆转的药物 细胞衰老(衰老药物)已经被开发出来，其中三种药物正在进行人体临床试验。 一种廉价的、全动物的Seno药物作用模型的获得将加速 阿尔茨海默病的新疗法。 背景：Seno药物通过一种常见的药理作用改善许多与年龄相关的病理。 作用：选择性地杀死或改变衰老细胞。Seno药物预计将推迟多样化 人类死亡的原因包括帕金森氏病、阿尔茨海默病和动脉粥样硬化，以及 癌症转移和复发。我们建议研究Seno药物，目标是三个不同的途径。这些 途径导致不同的反应，其特征是不同水平的AMP激酶和P53。 已对线虫转基因菌株进行了改造，以表达导致淀粉样蛋白的人类淀粉样蛋白- β(Aβ)和tau。我们发现，使用Seno药物(Piperlong Umine)治疗可以延长患者的寿命 表达β的转基因虫株的野生型和延迟性麻痹 具体目标1.确定其他Seno药物是否抑制Aβ和/或tau毒性。 内容提要：我们建议监测Seno药物对线虫的疗效。我们将利用 野生型，以及Aβ和tau转基因菌株。将评估几个结果参数： Aβ和tau毒性的改善、寿命、健康寿命、生育、发育和行为分析。 特定目的2.线虫中Seno作用的分子研究。 摘要：我们将研究P53和AMPK在衰老的野生型线虫中的表达。 如果没有使用Seno药物。虫子将在4、7和11天龄时收获。这将使我们能够 为了比较由于Seno治疗而导致的老化线虫中这些蛋白质的水平，例如在 衰老的哺乳动物细胞。线虫将很好地用于详细的分子研究，因为我们的 调查结果。 特定目的3.RNA-Seq转录组分析。 简介：使用下一代DNA测序的RNA-Seq将被用来检查转录组 对Seno药物治疗的反应变化。

PROJECT SUMMARY/ABSTRACT Significance: Cell senescence is implicated in many age-related diseases. Drugs which postpone or reverse cellular senescence (SENO drugs) have been developed and three of these drugs are in human clinical trials. The availability of an inexpensive, whole-animal model of SENO drug action will accelerate development of new treatments of Alzheimer’s Disease. Background: SENO drugs ameliorate numerous age-related pathologies through a common pharmacological action: the selective killing or alteration of senescent cells. SENO drugs are expected to postpone diverse causes of human mortality including Parkinson’s Disease, Alzheimer’s Disease, and atherosclerosis, as well as cancer metastasis and recurrence. We propose to study SENO drugs, targeting three distinct pathways. These pathways lead to alternative responses characterized by distinct levels of AMP Kinase and P53. C. elegans transgenic strains have been engineered to express the amyloidogenic human proteins amyloid- beta (Aβ) and tau. We found that treatment with a SENO drug (piperlongumine) resulted in longer life in the wild-type and postponed paralysis in Aβ-expressing transgenic worm strains. Specific Aim 1. Determine if other SENO drugs suppress Aβ and/or tau toxicity. Synopsis: We propose to monitor the efficacy of SENO drugs in the nematode C. elegans. We will utilize the wild-type, as well as Aβ and tau transgenic strains. Several outcome parameters will be assessed: amelioration of Aβ and tau toxicity, longevity, health-span, fertility, development, and analyses of behavior. Specific Aim 2. Molecular studies of SENO action in C. elegans. Synopsis: We will characterize the expression of P53 and AMPK in aging wild-type C. elegans with and without the application of SENO drugs. Worms will be harvested at 4, 7, and 11 days of age. This will allow us to compare the levels of these proteins in aging C. elegans due to SENO treatments, such as those in senescent mammalian cells. C. elegans will lend itself well to detailed molecular studies consequent to our findings. Specific Aim 3. Transcriptome analysis by RNA-Seq. Synopsis: RNA-Seq, using next-generation DNA sequencing, will be used to examine the transcriptome changes in response to SENO drug treatments.