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: 10418204
• 负责人: James R Cypser
• 金额: $ 14.37万
• 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/10418204
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Atherosclerosis; Caenorhabditis elegans; Cell Aging; Cell model; Cells; Clinical Trials; Development; Disease; Drug Targeting; Engineering; Genetic Transcription; Human; Lead; Life; Nematoda; Neoplasm Metastasis; Paralysed; Parkinson Disease; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Preclinical Testing; TP53 gene; Testing; Therapeutic Agents; Toxic effect; Transgenic Organisms; adenylate kinase; age related; cancer recurrence; cell type; drug action; human mortality; molecular diagnostics; response; senescence; single-cell RNA sequencing; tau Proteins

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, and have since found a similar effect with a second SENO drug (KU60019). We propose to extend these studies by applying a representative set of five SENO drugs to wild-type nematodes and then apply single-cell RNA-Seq, to search for common seno-drug-driven transcriptional changes within and between specific cell types. 6

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。药物 已开发了推迟或反向细胞感染（Seno Drugs），其中三个 药物正在人类临床试验中。 Seno的便宜，全动物模型的可用性 药物作用将加速发展阿尔茨海默氏病的新疗法。 背景：Seno药物通过常见来改善许多与年龄相关的病理 药理作用：选择性杀死或改变感觉细胞。 Seno毒品是 预计将推迟潜水员的人类死亡率，包括帕金森氏病， 阿尔茨海默氏病，动脉粥样硬化以及癌症转移和复发。我们 研究Seno药物的建议，针对三种不同的途径。这些途径导致 替代反应以不同水平的AMP激酶和p53为特征。 秀丽隐杆线虫转基因菌株已被设计为表达淀粉样蛋白生成的人 蛋白质淀粉样蛋白β（Aβ）和tau。我们发现使用Seno药物（哌LUMINE）治疗 在表达Aβ的转基因蠕虫中，野生型和推迟瘫痪导致了更长的寿命 菌株，此后发现了第二种Seno药物（KU60019）也有类似的作用。我们建议 通过将五种Seno药物的代表性集用于野生型来扩展这些研究 线虫，然后应用单细胞RNA-seq，以搜索常见的seno-prug驱动 特定细胞类型内和之间的转录变化。 6