Combining pharmacology & AI to identify novel targets controlling proteostasis in neuronal cells

神经退行性疾病（NDs）是一种与异常健康衰老相关的衰弱性疾病，是BBSRC关注的重点。虽然NDs的分子起源是多方面的，但涉及蛋白质合成、折叠和运输的蛋白质稳态网络的失调是NDs进展的核心。这导致细胞压力导致细胞死亡。在分子水平上，人们认为病理性聚集体的积累是由于易于错误折叠的蛋白质的非生理性聚集造成的，其积累是由于蛋白质稳定系统（包括蛋白酶体、线粒体功能障碍、应激和自噬系统）中与年龄相关的缺陷。我们的假设是，尽管每个ND涉及不同的罪魁祸首蛋白；共同调控节点的存在驱动了蛋白质稳态的变化。我们的目标是使用先前开发的NDs的iPS细胞模型来确定调节神经元细胞中蛋白质停滞的靶标。我们将通过利用Sosei-Heptares的内部人工智能和药物发现平台以及定义明确的内部专有化合物来实现这一目标。

Neurodegenerative diseases (NDs) are debilitating conditions linked with aberrant health aging, akey BBSRC focus. Whilst the molecular origins for NDs are multiple, the dysregulation of proteinhomeostasis -or proteostasis- network, involving protein synthesis, folding & trafficking, is centralto the progression of NDs. This results in cellular stresses leading to cell death. At the molecularlevel, it is assumed that the accumulation of pathological aggregates result from non-physiologicalaggregation of proteins prone to misfolding, accumulating due to age-related deficits in proteostaticsystems, including the proteasome, mitochondrial dysfunction, stress & autophagic system.Our hypothesis is that although each ND involves distinct culprit proteins; commonregulatory nodes exist driving changes in protein homeostasis. Our aim is to use previouslydeveloped iPS cell models of NDs to identify targets for modulating proteostasis in neuronalcells. We will achieve this by harnessing Sosei-Heptares' in house AI & drug discoveryplatform coupled with well defined in house proprietary compounds.