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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.

项目总结