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

项目概要/摘要 意义：细胞衰老与许多与年龄相关的疾病有关。 推迟或逆转细胞衰老（SENO 药物）已经开发出来，其中三种 药物正在进行人体临床试验 廉价的 SENO 全动物模型的可用性。 药物作用将加速阿尔茨海默病新疗法的开发。 背景：SENO 药物通过一种常见的方法改善许多与年龄相关的病症。 药理作用：选择性杀伤或改变衰老细胞的药物。 预计将推迟导致人类死亡的多种原因，包括帕金森病， 阿尔茨海默病、动脉粥样硬化以及癌症转移和复发。 研究 SENO 药物，针对这些不同的途径。 以不同水平的 AMP 激酶和 P53 为特征的替代反应。 秀丽隐杆线虫转基因菌株已被改造为表达人类淀粉样蛋白 我们发现用 SENO 药物（piperlongumine）治疗可以改善β淀粉样蛋白（Aβ）和 tau 蛋白。 延长了野生型的寿命，并延迟了表达 Aβ 的转基因蠕虫的瘫痪 菌株，并且此后发现第二种 SENO 药物 (KU60019) 具有类似的效果。 通过将一组具有代表性的五种 SENO 药物应用于野生型来扩展这些研究 线虫，然后应用单细胞RNA-Seq，寻找常见的seno-drug-driven 特定细胞类型内部和之间的转录变化。 6