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

C. 线虫作为细胞衰老和阿尔茨海默病的模型

• 批准号: 10261332
• 负责人: James R Cypser
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261332
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Animals; Ataxia; Atherosclerosis; Behavior; Caenorhabditis elegans; Cell Aging; Cell Survival; Cell model; Cell secretion; Cells; Cessation of life; Clinical Trials; Cognitive deficits; Complex; Consumption; DNA sequencing; Dasatinib; Development; Disease; Down-Regulation; Drug Targeting; Engineering; Fertility; Foundations; Future; Generations; Genetic Transcription; Goals; Harvest; Human; Huntington Disease; Inflammation; Investigation; Knowledge; Lead; Life; Life Expectancy; Longevity; Mammalian Cell; Mammals; Measurement; Measures; Modeling; Molecular; Molecular Target; Monitor; Mus; Nematoda; Neoplasm Metastasis; Organism; Outcome; Paralysed; Parkinson Disease; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Pharmacotherapy; Preclinical Testing; Prevention; Proteins; Quercetin; RNA analysis; Reporting; Research; Resistance; Role; Stress; System; TP53 gene; Testing; Therapeutic Agents; Time; Toxic effect; Transcript; Transgenic Organisms; Whole Organism; abeta toxicity; adenylate kinase; age related; base; cancer recurrence; cost; differential expression; drug action; drug mechanism; healthspan; human disease; human mortality; inducible gene expression; molecular diagnostics; mouse model; mutant; next generation; novel; novel drug class; novel strategies; novel therapeutics; protein expression; response; senescence; side effect; tau Proteins; transcriptome; transcriptome sequencing

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.

项目摘要/摘要 意义：许多与年龄相关的疾病中隐含细胞的感应。推迟或反向的药物 已经开发了细胞感染（Seno药物），其中三种在人类临床试验中。 Seno药物作用的廉价，全动物模型的可用性将加速 阿尔茨海默氏病的新疗法。 背景：Seno药物通过常见的药物改善许多与年龄有关的病理 动作：选择性杀死或改变感觉细胞。预计Seno药物将推迟潜水员 人类死亡率的原因，包括帕金森氏病，阿尔茨海默氏病和动脉粥样硬化以及 癌症转移和复发。我们建议研究针对三种不同途径的Seno药物。这些 途径导致替代反应，其特征是不同水平的AMP激酶和p53。 秀丽隐杆线虫转基因菌株已被设计为表达淀粉样蛋白蛋白淀粉样蛋白 beta（Aβ）和tau。我们发现用Seno药物（哌luminine）的治疗导致了更长的寿命 野生型和推迟表达Aβ的转基因蠕虫菌株中的瘫痪。 具体目标1。确定其他Seno药物是否抑制Aβ和/或TAU毒性。 简介：我们建议监测线虫秀丽隐杆线虫中Seno药物的效率。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： 改善Aβ和TAU毒性，寿命，健康跨度，生育能力，发育和行为分析。 特定目的2。秀丽隐杆线虫中SENO作用的分子研究。 简介：我们将表征p53和ampk在衰老的野生型秀丽隐杆线虫中的表达和 没有使用Seno药物。蠕虫将在4、7和11天大时收获。这将使我们 比较由于seno治疗而导致的e秀隐杆线虫中这些蛋白质的水平，例如 感觉哺乳动物细胞。秀丽隐杆线虫将非常适合我们的详细分子研究 发现。 特定目标3。通过RNA-Seq进行转录组分析。 概要：使用下一代DNA测序的RNA-Seq将用于检查转录组 响应于Seno药物治疗的变化。