Regulation of Membrane Lipid Homeostasis

膜脂质稳态的调节

• 批准号: 10623581
• 负责人: PETER J. ESPENSHADE
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623581
• 关键词: Address; Adult; CRISPR/Cas technology; Cell membrane; Cell physiology; Cells; Cellular biology; Cholesterol; Endocytosis; Fatty Acids; Genes; Genetic; Homeostasis; Human; Integral Membrane Protein; Intervention; Learning; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mammalian Cell; Membrane; Membrane Biology; Membrane Lipids; Pathway interactions; Permeability; Proteome; Regulation; Research; United States; fluidity; forward genetics; heart disease prevention; hypercholesterolemia; lipid transport; model organism; new therapeutic target; receptor function

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.

项目摘要 细胞膜的脂质成分控制着双层的通透性和流动性，以及折叠和 整体膜蛋白的活性，约占人类蛋白质组的30%。因此，脂类 膜的组成受到严格的动态平衡控制。在过去的60年里，我们学到了一个 关于膜脂细胞生物学的大量资料，主要来自模型生物，因为 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 人类细胞的这些细胞功能，开启了哺乳动物细胞遗传学的新纪元。 我们的Mira研究战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， 特别注重调节膜脂的动态平衡。在未来5年，我们将使用 遗传学来解决两个挑战。对于挑战1，我们将确定新的质膜调节剂 脂类成分。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 鉴定同化低密度脂蛋白(LDL)衍生脂肪酸所需的基因。 总体而言，这些拟议的米拉研究将对膜生物学领域做出根本性贡献， 细胞内脂质转运、低密度脂蛋白受体功能/内吞作用、SREBP途径和脂质调节 综合。鉴于胆固醇合成和低密度脂蛋白受体功能的调节是主要干预措施 在治疗高胆固醇血症方面，这些研究可能为预防找到新的治疗靶点。 心脏病是美国成年人的头号杀手。