CARD - Senescent Phenotypes of Isogenic iPSC-Derived Alzheimer's Disease and Related Dementia Models at Cellular Resolution

CARD - 细胞分辨率下同基因 iPSC 衍生的阿尔茨海默病和相关痴呆模型的衰老表型

• 批准号: 10913051
• 负责人: Nathan Basisty
• 金额: $ 4.47万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913051
• 关键词: ADAMTS; Aging; Alzheimer' s disease related dementia; Cell Aging; Cells; Data; Databases; Dose; Doxorubicin; Engineering; Genes; Genetic Risk; Genetic Variation; Genotoxic Stress; Heritability; Image; Individual; Induced pluripotent stem cell derived neurons; Laboratories; Link; Modeling; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Phenotype; Population Heterogeneity; Proteins; Proteomics; Research Personnel; Resolution; Resources; Risk; Sampling; Testing; Work; brain cell; cell type; extracellular vesicles; genetic variant; induced pluripotent stem cell; insight; multiple omics; prion-like; repository; response; risk variant; senescence; single-cell RNA sequencing; transcriptomics; transmission process

Toward our aim of determining which genetic risk variants of ADRD sensitive cells to senescence, we have created a pilot experimental plan for the establishment and optimization of iPSC-derived neuronal senescence in the KOLF2.1j parental line. Using genotoxic stress induced by doxorubicin treatment, we found the optimal dose of senescence to induce a stable senescent phenotype in culture is between 25nm to 50nm. We have prepared proteomic and transcriptomic samples accross the entire dose response, as well as imaging data to confirm the presence of senescence signatures. From the resulting data, we will develop multi-omic (proteomic and transcriptomic) signatures of senescence in neurons, and then systematically test the propensity of other ADRD risk variant-engineered cells to become senescent based on these signatures. The proposed work would systematically test whether genetic variants associated with ADRD are mechanistically linked to cellular senescence as a potential driver of aging.

为了确定ADRD敏感细胞对衰老的遗传风险变异的目的，我们为在Kolf2.1J父母系列中建立和优化IPSC衍生的神经元衰老的试验实验计划。使用阿霉素治疗诱导的遗传毒性应激，我们发现在培养物中诱导稳定的衰老表型的最佳衰老剂量在25nm至50nm之间。我们已经准备好了整个剂量反应的蛋白质组学和转录样品，以及成像数据以确认衰老特征的存在。从所得数据中，我们将开发神经元中衰老的多摩变（蛋白质组学和转录组）特征，然后系统地测试其他ADRD风险变体细胞的倾向，以根据这些特征来成为衰老。所提出的工作将系统地测试与ADRD相关的遗传变异与细胞衰老有关，作为衰老的潜在驱动力。