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。这些药物 延缓或逆转细胞衰老(衰老药物)已经开发出来，其中三种 药物正在进行人体临床试验。一种廉价的全动物模型Seno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 药理作用：选择性地杀死或改变衰老细胞。Seno毒品是 预计将推迟包括帕金森氏症在内的多种人类死亡原因， 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。这些路径通向 不同的反应以不同水平的AMP激酶和P53为特征。 线虫转基因株已被改造成表达淀粉样变性的人 淀粉样β蛋白(Aβ)和tau。我们发现使用一种Seno药物(胡椒碱)进行治疗 在表达β的转基因蠕虫中导致野生型和延迟性瘫痪的更长寿命 自那以后，第二种Seno药物(KU60019)也发现了类似的效果。我们建议 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，寻找共同的药物驱动 特定细胞类型内部和之间的转录变化。 6.

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