Molecular mechanisms for lipid sensing by mTORC1

mTORC1 脂质传感的分子机制

基本信息

批准号：
10393506
负责人：
Roberto Zoncu
金额：
$ 35.73万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393506
关键词：
Address Amino Acids Area Autophagocytosis Binding Biological Assay Catabolic Process Cells Cellular Membrane Cellular biology Cholesterol Cholesterol Homeostasis Complex Cytoplasm Diabetes Mellitus Disease Endoplasmic Reticulum FRAP1 gene Glucose Goals Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Homeostasis In Vitro Integral Membrane Protein Knowledge Laboratories Lead Lipids Location Lysosomes Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Measurement Measures Mediating Metabolic Metabolic Diseases Molecular Nerve Degeneration Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nucleotide Biosynthesis Nutrient Organelles Oxygen Patients Phosphotransferases Population Process Protein Biosynthesis Protein Kinase Proteins Regulation Research Role Signal Pathway Signal Transduction Site Stimulus Supraoptic Vertical Ophthalmoplegia Surface Testing Therapeutic base detection of nutrient driving force human disease in vivo innovation insight lipid biosynthesis lysosomal proteins novel strategies novel therapeutic intervention oxysterol binding protein prevent programs reconstitution recruit repaired response restoration sensor stem

项目摘要

PROJECT SUMMARY The molecular mechanisms through which cells sense nutrients remain largely unknown, but their elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of Rapamycin Complex 1 (mTORC1). In response to the combined action of metabolic inputs such as nutrients, growth factors, energy and oxygen, mTORC1 translocates from the cytoplasm to the surface of lysosomes, where its kinase function becomes activated. Accumulating evidence indicates that aberrant mTORC1 activation at the lysosome could be a driving force in diseases ranging from cancer to type-2 diabetes to neurodegeneration. Thus, a deep mechanistic understanding of how mTORC1 is activated in response to nutrients could point the way to novel therapeutic strategies in these diseases. The current proposal investigates a central aspect of mTORC1 function that has so far remained understudied and poorly understood, namely, its ability to sense lipids. We will build on our recent discovery that mTORC1 senses an important lipid, cholesterol, at the lysosome. Using innovative approaches both in cells and in vitro, we will address and elucidate key aspects of newly identified signaling pathway. In particular, we will determine i) the cellular location of the cholesterol pools that regulate mTORC1 ii) the transport circuits that make cholesterol available to mTORC1 and iii) the molecular mechanisms through which cholesterol induces mTORC1 recruitment to the lysosomal surface. Moreover, we will investigate how cholesterol sensing by mTORC1 depends on the Niemann-Pick C1 protein, loss of which causes a fatal metabolic and neurodegenerative disease. We will address these research aims via innovative and highly complementary approaches recently optimized in our lab, including measurement and targeted manipulations of the lipid content of selected organelle populations, combined with reconstitution-based assays of mTORC1 regulation. Our findings will impact the current understanding of the molecular mechanisms of cellular lipid homeostasis, and will point the way to novel approaches to manipulate mTORC1 signaling in disease settings.

项目概要细胞感知营养物质的分子机制仍然很大程度上未知，但它们的阐明是我们理解正常和疾病状态下代谢调节的关键。在中心营养感应和生长调节是一种古老的蛋白激酶，被称为机械靶标雷帕霉素复合物 1 (mTORC1)。为了响应营养物质等代谢输入的综合作用，生长因子、能量和氧气，mTORC1从细胞质易位到溶酶体表面，其激酶功能被激活。越来越多的证据表明异常的 mTORC1 激活溶酶体可能是癌症、2 型糖尿病等疾病的驱动力神经变性。因此，深入了解 mTORC1 如何响应营养素可以为这些疾病的新治疗策略指明道路。目前的提案研究了 mTORC1 功能的一个核心方面，迄今为止该功能仍然存在人们对它感知脂质的能力知之甚少。我们将基于我们最近的发现 mTORC1 在溶酶体中感知一种重要的脂质——胆固醇。在细胞和在体外，我们将解决并阐明新发现的信号通路的关键方面。特别是，我们将确定 i) 调节 mTORC1 的胆固醇库的细胞位置 ii) 使 mTORC1 可利用的胆固醇和 iii) 胆固醇诱导 mTORC1 的分子机制募集到溶酶体表面。此外，我们将研究 mTORC1 如何感知胆固醇取决于 Niemann-Pick C1 蛋白，该蛋白的丢失会导致致命的代谢和神经退行性病变疾病。我们最近将通过创新和高度互补的方法来解决这些研究目标在我们的实验室中进行优化，包括对选定细胞器的脂质含量进行测量和有针对性的操作群体，结合基于重构的 mTORC1 调节测定。我们的研究结果将影响目前对细胞脂质分子机制的理解稳态，并将为在疾病环境中操纵 mTORC1 信号传导的新方法指明道路。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NBEAL1 controls SREBP2 processing and cholesterol metabolism and is a susceptibility locus for coronary artery disease.

NBEAL1 控制 SREBP2 加工和胆固醇代谢，是冠状动脉疾病的易感基因座。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Bindesbøll, Christian;Aas, Aleksander;Ogmundsdottir, Margret Helga;Pankiv, Serhiy;Reine, Trine;Zoncu, Roberto;Simonsen, Anne
通讯作者：
Simonsen, Anne