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Signal Transduction by PI3K/Akt/mTOR Pathway

通过 PI3K/Akt/mTOR 途径进行信号转导

基本信息

批准号：
9108384
负责人：
Jin Zhang
金额：
$ 30.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108384
关键词：
1-Phosphatidylinositol 3-Kinase 3T3-L1 Cells Address Adipocytes Amino Acids Biochemical Biological Models Biosensor Cell Nucleus Cell membrane Cell model Cell physiology Clinical Complex Development Diabetes Mellitus Disease Dissociation Engineering FRAP1 gene Family member Fibroblasts Fluorescence Microscopy Fluorescence Resonance Energy Transfer Goals Growth Guanosine Triphosphate Phosphohydrolases Health Image Insulin Lead Membrane Membrane Microdomains Metabolic syndrome Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Oxygen Pathway interactions Phosphatidylinositols Phosphorylation Play Process Protein Isoforms Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Regulation Reporter Research Resolution Role Series Signal Pathway Signal Transduction Signaling Molecule Specificity Surface TCL1B gene Testing Therapeutic Tissues acid stress base cell growth regulation effective therapy insight novel therapeutic intervention phosphoinositide-dependent kinase 1

项目摘要

DESCRIPTION (provided by applicant): The signaling pathway regulated by phosphatidylinositol 3-kinase (PI3K) and the downstream serine/threonine kinase Akt (also known as protein kinase B) transduces the signals encoded by insulin and growth factors and regulates a number of processes that are critical to cell physiology. In addition to serving as a critical downstream component in the PI3K/Akt pathway, the mechanistic target of rapamycin (mTOR) also integrates signals from amino acids, stress, oxygen and energy level to impact most major cellular functions. For such key-node signaling molecules as PI3K, Akt and mTOR, which regulate multiple cellular processes, spatial compartmentalization has been suggested to be an important mechanism for achieving high signaling specificity. In particular, accumulating evidence has suggested that spatial compartmentalization is not only important for enhancing signaling specificity, it is also required for the functioning of the PI3K/Akt/mTOR signaling pathway. However, spatial regulation of PI3K/Akt/mTOR signaling is not well defined and the underlying mechanisms remain poorly understood. The overall goal of our research is to elucidate the molecular and cellular mechanisms by which the PI3K/Akt/mTOR pathway is spatially regulated. We have performed a series of preliminary studies that focus on the plasma membrane and nuclear regulation of this pathway, which led to the hypothesis that signaling activities of the PI3K/Akt/mTOR pathway are present and specifically regulated in both plasma membrane and nuclear compartments. In this proposal, building upon our preliminary findings, we will use NIH3T3 fibroblasts, 3T3 L1 adipocytes, and primary mouse adipocytes as cellular model systems, and combine biochemical and functional characterization with biosensor engineering and super-resolution fluorescence microscopy to address the following aims: 1) To investigate spatial compartmentalization of phosphoinositides.; 2) To examine cellular regulation of Akt; 3) To determine the mechanisms that regulate mTORC1 activities in subcellular compartments. Dysregulated PI3K/Akt/mTOR signaling has widespread implications for clinical conditions. In insulin-responsive tissues, the pathway plays a pivotal role for the effects of insulin, and impaired signaling through PI3K/Akt/mTOR may predispose to the development of diabetes. A mechanistic understanding of signal transduction by PI3K/Akt/mTOR is crucial to developing therapeutic approaches for these clinical conditions.