Connecting myelin membrane turnover with antigen presenting cells and autoimmunity (A10)

该项目的主要目的是确定脂质毒性和脱髓鞘疾病的发病机制之间的联系。A10提出小胶质细胞中的脂质过载可诱导适应不良的免疫应答。在当前的资助期内，A10发现胆固醇晶体在诱导脱髓鞘事件后在小胶质细胞/巨噬细胞中形成。 这种晶体在溶酶体中产生，并可能触发溶酶体破裂，激活炎性小体复合体并诱导细胞凋亡。 这个项目将测试胆固醇超载和晶体形成是否会损害脱髓鞘病变的组织修复。将测试如何促进脂质从脱髓鞘病变流出以促进髓鞘再生和保护神经元免于变性的新实验策略。

The project primarily aims to identify a connection between lipid toxicity and the pathogenesis of demyelinating diseases. A10 proposes that lipid overloading in microglia can induce a maladaptive immune response. In the current funding period A10 found that cholesterol crystals are formed in microglia/macrophages after inducing a demyelinating event. Such crystals are generated in lyosomes and may trigger lysosomal rupture, activate the inflammasome complex and induce pyroptosis. This project will test whether cholesterol overloading and crystal formation impairs tissue repair in demyelinating lesions. Novel experimental strategies of how to promote lipid efflux from demyelinating lesions in order to promote remyelination and protect neurons from degeneration will be tested.