Tuberous sclerosis complex in memory formation

结节性硬化症在记忆形成中的作用

基本信息

批准号：
7323678
负责人：
PRAMOD K DASH
金额：
$ 32.48万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7323678
关键词：
1-Phosphatidylinositol 3-Kinase 5&apos -AMP-activated protein kinase 70-kDa Ribosomal Protein S6 Kinases AICA ribonucleotide Abbreviations Adenosine Monophosphate Attention Behavioral Binding Binding Proteins Biochemical Genetics Brain Brain-Derived Neurotrophic Factor CREB1 gene Calcium Cell Surface Receptors Cells Complex Computer information processing Cultured Cells Cyclic AMP-Responsive DNA-Binding Protein Development Event Extracellular Signal Regulated Kinases Glucose Hippocampus (Brain)Homologous Gene Infusion procedures Knockout Mice Laboratories Learning Localized Mediating Memory Memory Disorders Memory impairment Messenger RNA Mitogen-Activated Protein Kinases Molecular Mus NF-kappa B Nerve Growth Factor Receptors Neurons Neurotransmitters Pathway interactions Phosphatidylinositols Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Phosphotransferases Protein Kinase Proteins Proto-Oncogene Proteins c-akt RAC-Alpha Serine/Threonine Kinase Regulation Research Personnel Ribosomal Protein S6 Kinase Role Signal Transduction Sirolimus Site Small Interfering RNA Testing Training Translations Tuberous sclerosis protein complex attenuation experience genetic regulatory protein human TSC2 protein improved inhibitor/antagonist innovation multidisciplinary neurotrophic factor novel strategies phospholipase C gamma platelet protein P47 programs receptor receptor coupling research study response rho sensor therapy development tumor

1-Phosphatidylinositol 3-Kinase 5&apos -AMP-activated protein kinase 70-kDa Ribosomal Protein S6 Kinases AICA ribonucleotide Abbreviations Adenosine Monophosphate Attention Behavioral Binding Binding Proteins Biochemical Genetics Brain Brain-Derived Neurotrophic Factor CREB1 gene Calcium Cell Surface Receptors Cells Complex Computer information processing Cultured Cells Cyclic AMP-Responsive DNA-Binding Protein Development Event Extracellular Signal Regulated Kinases Glucose Hippocampus (Brain)Homologous Gene Infusion procedures Knockout Mice Laboratories Learning Localized Mediating Memory Memory Disorders Memory impairment Messenger RNA Mitogen-Activated Protein Kinases Molecular Mus NF-kappa B Nerve Growth Factor Receptors Neurons Neurotransmitters Pathway interactions Phosphatidylinositols Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Phosphotransferases Protein Kinase Proteins Proto-Oncogene Proteins c-akt RAC-Alpha Serine/Threonine Kinase Regulation Research Personnel Ribosomal Protein S6 Kinase Role Signal Transduction Sirolimus Site Small Interfering RNA Testing Training Translations Tuberous sclerosis protein complex attenuation experience genetic regulatory protein human TSC2 protein improved inhibitor/antagonist innovation multidisciplinary neurotrophic factor novel strategies phospholipase C gamma platelet protein P47 programs receptor receptor coupling research study response rho sensor therapy development tumor

展开

项目摘要

DESCRIPTION (provided by applicant): This is the second revision of a proposal entitled "Tuberous Sclerosis Complex in Memory Formation". Elucidation of the molecular events underlying the formation and storage of memory is not only relevant for understanding information processing in the brain but also for the development of therapies to treat memory disorders. Memory formation is initiated by neurotransmitters and neurotrophic factors released as a result of neuronal activity during the learning experience. Engaged neurotrophic receptors activate three key intracellular signaling cascades: Ras-Erk, PLCgamma and PI3-kinase. Although the PLCgamma and Ras- Erk pathways have been extensively examined in long-term spatial memory formation, the role of the equally important PI3K cascade in memory formation has received less attention. Recent genetic and biochemical experiments show that tuberous sclerosis protein -2 (TSC2) is phosphorylated by AKT, a key protein kinase activated by PI3K. The TSC1-TSC2 complex regulates the activity of the mammalian target for rapamycin (mTOR), which increases translation of specific mRNA through its action on ribosomal S6 kinase (S6K, also called p70s6k) and/or 4EBP1 (4E binding protein 1). The dominant role of mTOR in PI3K signaling is evident from experimental findings demonstrating that tumors caused by constitutive activation of the PI3K cascade can be targeted by rapamycin, a highly selective inhibitor for mTOR. In addition to its regulation by AKT phosphorylation, the TSC-mTOR pathway is regulated by adenosine monophosphate-activated kinase (AMPK) which acts as an energy sensor for the cell. In this proposal, we will examine in Specific Aim 1: if the TSC-mTOR pathway is activated following training and is required for spatial memory storage in the hippocampus, in Specific Aim 2: if the memory enhancing effect of glucose is in part acting through the TSC- mTOR pathway in the hippocampus, and in Specific Aim 3: if conditional tsc2 (-/-) mice have impaired spatial memory, and if these impairments can be rescued by manipulation of the mTOR pathway. The results from this study will reveal key molecular events that participate in spatial memory by investigating the activity and role of the TSC-mTOR pathway in the hippocampus. The results from these studies will provide a crucial step towards development of pharmacological and/or molecular strategies to treat memory disorders.

描述（由申请人提供）：这是一项名为“记忆形成中的结节性硬化症复合物”的提案的第二个修订版。阐明记忆形成和存储基础的分子事件不仅与理解大脑中的信息处理有关，还与治疗记忆障碍的疗法的发展有关。记忆形成是由神经递质和在学习经历过程中神经元活性释放的神经营养因素引发的。参与的神经营养受体激活三个关键的细胞内信号传导级联：RAS-ERK，PLCGAMMA和PI3-激酶。尽管已在长期的空间记忆形成中广泛研究了plcgamma和raserk途径，但同样重要的PI3K级联对于记忆形成中的作用却较少。最近的遗传和生化实验表明，结核性硬化蛋白-2（TSC2）被Akt磷酸化，Akt是PI3K激活的关键蛋白激酶。 TSC1-TSC2复合物调节乳腺霉素（MTOR）的哺乳动物靶点的活性，该靶标通过其对核糖体S6激酶（S6K，也称为P70S6K）和/或4EBP1（4E结合蛋白1）的核糖体S6激酶（S6K，也称为P70S6K）来增加对特定mRNA的翻译。 MTOR在PI3K信号传导中的主要作用可以从实验发现中可以明显看出，这表明由PI3K级联反应引起的肿瘤可以由Rapamycin（MTOR高度选择性抑制剂）靶向。除了通过AKT磷酸化调节，TSC-MTOR途径还受腺苷单磷酸激活的激酶（AMPK）调节，该激酶（AMPK）充当细胞的能量传感器。在该提议中，我们将在特定目标中检查1：如果在训练后激活TSC-MTOR途径，并且在海马中需要空间记忆存储所必需通过操纵MTOR途径救出。这项研究的结果将揭示通过研究海马中TSC-MTOR途径的活性和作用来参与空间记忆的关键分子事件。这些研究的结果将为制定治疗记忆障碍的药理和/或分子策略提供至关重要的步骤。