Regulation of Membrane Lipid Homeostasis

项目摘要 细胞膜的脂质组成控制双层的渗透性和流动性以及细胞膜的折叠和 整合膜蛋白的活性，其占人类蛋白质组的约30%。因此，脂质 膜的组成受到严格的稳态控制。在过去的60年里，我们学到了一个 大量关于膜脂细胞生物学的知识，主要来自模式生物， 培养的人类细胞的遗传学仍然具有挑战性。CRISPR技术现在允许直接检查 这些细胞功能在人类细胞，开辟了哺乳动物细胞遗传学的新时代。 我们的MIRA研究策略是将哺乳动物细胞遗传学应用于细胞生物学中长期存在的问题， 特别关注膜脂质稳态的调节。未来5年，我们将利用 遗传学解决两个挑战。对于挑战#1，我们将确定新的质膜调节剂， 脂质组成。对于挑战#2，我们将通过以下方式发现溶酶体脂肪酸输出的机制： 表征同化低密度脂蛋白（LDL）衍生脂肪酸所需的基因。 总的来说，这些拟议的MIRA研究将为膜生物学领域做出根本性贡献， 细胞内脂质转运、LDL受体功能/内吞作用、SREBP通路和脂质调节 合成.鉴于调节胆固醇合成和LDL受体功能是主要干预措施， 在高胆固醇血症的治疗中，这些研究可能会发现新的治疗靶点， 心脏病是美国成年人的头号杀手。

Project Summary The lipid composition of cell membranes controls bilayer permeability and fluidity as well as the folding and activity of integral membrane proteins, which comprise ~30% of the human proteome. Consequently, the lipid composition of membranes is subject to tight homeostatic control. Over the past 60 years, we have learned a tremendous amount about membrane lipid cell biology, largely from model organisms because forward genetics in cultured human cells remained challenging. CRISPR technology now permits a direct examination of these cellular functions in human cells, opening up a new era of mammalian cell genetics. Our MIRA research strategy is to apply mammalian cell genetics to long-standing questions in cell biology, specifically focusing on the regulation of membrane lipid homeostasis. Over the next 5 years, we will use genetics to address two challenges. For Challenge #1, we will identify new regulators of plasma membrane lipid composition. For Challenge #2, we will discover the mechanism of lysosomal fatty acid export by characterizing genes required for the assimilation of low-density lipoprotein (LDL)-derived fatty acids. Overall, these proposed MIRA studies will make fundamental contributions to the fields of membrane biology, intracellular lipid transport, LDL receptor function/endocytosis, the SREBP pathway, and regulation of lipid synthesis. Given that modulation of cholesterol synthesis and LDL receptor function are primary interventions in the treatment of hypercholesterolemia, these studies may identify new therapeutic targets for the prevention of heart disease, a leading killer of adults in the United States.