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

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

展开

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.

描述（由适用提供）：由磷脂酰肌醇3-激酶（PI3K）调节的信号通路和下游的串行/苏氨酸激酶Akt（也称为蛋白激酶B）翻译了由胰岛素和生长因子编码的信号，并调节了关键对细胞物理学的过程。除了作为PI3K/AKT途径中的关键下游成分外，雷帕霉素（MTOR）的机械靶标还整合了来自氨基酸，应力，氧气和能级的信号，以影响大多数主要的细胞功能。对于调节多个细胞过程的PI3K，AKT和MTOR（AKT和MTOR）等键节点的信号分子，已经认为空间隔室化是实现高信号特异性的重要机制。特别是，累积的证据被认为，空间隔室不仅对于增强信号特异性很重要，而且PI3K/AKT/MTOR信号通路的功能也是必需的。但是，PI3K/AKT/MTOR信号传导的空间调节尚未很好地定义，并且潜在机制仍然很少了解。我们研究的总体目标是阐明PI3K/AKT/MTOR途径在空间调节的分子和细胞机制。我们已经进行了一系列初步研究，这些研究重点介绍了该途径的质膜和核调节，这导致了以下假设：PI3K/AKT/MTOR途径的信号传导活性在质膜和核隔室中都存在，并特别调节。在这项提议中，基于我们的初步发现，我们将使用NIH3T3成纤维细胞，3T3 L1脂肪细胞和主要的小鼠脂肪细胞作为细胞模型系统，并将生物化学和功能性特征与生物传感器工程和超级分辨率荧光显微镜与下面的ARPATINS：1）进行了调查：1） 2）检查AKT的细胞调节； 3）确定调节亚细胞隔室中MTORC1活性的机制。 PI3K/AKT/MTOR信号传导的失调对临床条件具有宽度的影响。在胰岛素响应的时机中，该途径对胰岛素的作用起着关键作用，并且通过PI3K/AKT/MTOR的信号受损可能会易于发育。 PI3K/AKT/MTOR对信号转导的机械理解对于开发这些临床条件的治疗方法至关重要。