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

为了确定哪些ADRD敏感细胞的遗传风险变异对衰老有影响，我们为建立和优化KOLF2.1j亲本系中IPSC衍生的神经元衰老制定了一个中试实验计划。利用阿霉素诱导的遗传毒性胁迫，我们发现诱导稳定衰老表型的最佳衰老剂量为25~50 nm。我们已经准备了整个剂量反应的蛋白质组和转录组样本，以及确认衰老特征存在的成像数据。根据得到的数据，我们将开发神经元衰老的多组体(蛋白质组和转录组)特征，然后基于这些特征系统地测试其他ADRD风险变体工程细胞衰老的倾向。这项拟议的工作将系统地测试与ADRD相关的基因变异是否与作为衰老潜在驱动因素的细胞衰老有机械联系。

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.