REGULATION OF SYNAPSE AND NETWORK DYNAMICS BY MTOR

MTOR 对突触和网络动态的调节

• 批准号: 8791404
• 负责人: Matthew C Weston
• 金额: $ 8.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791404
• 关键词: Achievement; Affect; Animal Model; Architecture; Autistic Disorder; Behavioral; Brain; Calcium; Cell physiology; Cells; Cellular Structures; Code; Congenital Abnormality; Cytoplasmic Granules; Data; Development; Disease; Disease model; Drug Targeting; Electrophysiology (science); Energy Metabolism; Epilepsy; Equilibrium; Event; Faculty; Functional disorder; Gene Mutation; Genes; Genetic; Genome; Glutamates; Growth; Growth Factor; Hippocampus (Brain); Human; Image; Image Analysis; Intellectual functioning disability; Lead; Learning; Link; Mediating; Mediator of activation protein; Medicine; Mentors; Molecular; Molecular Abnormality; Mus; Mutation; Neurologic; Neurons; Nutrient; Pathway Analysis; Pathway interactions; Pharmacology; Phase; Phenotype; Physiological; Play; Population; Positioning Attribute; Process; Property; Proteins; Publications; Publishing; Raptors; Recruitment Activity; Regulation; Research; Research Institute; Role; Secure; Seizures; Signal Transduction; Sirolimus; Slice; Somatic Mutation; Subcellular structure; Suppressor Genes; Synapses; Synaptic Transmission; System; Techniques; Testing; Training; Translating; Translations; Work; arm; career; college; dentate gyrus; disease phenotype; excitatory neuron; human disease; inhibitory neuron; insight; macromolecule; mouse model; nervous system disorder; neural circuit; neurogenesis; neurotransmission; postsynaptic; presynaptic; prevent; programs; public health relevance; skills; small hairpin RNA; synaptic function; transmission process; two-photon

DESCRIPTION (provided by applicant): The mechanistic target of rapamycin (mTOR) signaling network plays a crucial role in cellular function, integrating information provided by growth factors, nutrient availability and synaptic input to regulate processes such as synthesis of macromolecules, energy metabolism and growth. Properly balanced mTOR signaling has proven to be particularly important in the brain, where mutations or deletions in several genes that code for proteins that regulate mTOR function are associated with autism, intellectual disability and epilepsy in humans and mouse models. Despite the strong link between the mTOR pathway and neurological disease, the mechanisms that lead from the genetic defects to phenotypes are still unknown. My previously published and preliminary data show that hyperactive mTOR signaling leads to altered synaptic transmission. Since changes in synaptic transmission can generate the altered network activity that results in neurological disorders, and especially seizures, this represents a possible mechanistic link between pathological mTOR activation and epilepsy. The scientific aims of this research plan are to better understand: 1) th regulation of synaptic transmission and connectivity by the mTOR signaling cascade, 2) the molecular events that mediate mTOR's effect on synaptic function, 3) how neurons that have altered mTOR signaling affect the function of the neural circuits in which they operate and 3) how these changes lead to network synchronizations that underlie epilepsy. The achievement of these objectives requires the integration of molecular, cellular and network-level approaches including: 1) electrophysiological analysis of synaptically connected, genetically-modified neuron pairs, 2) quantitative imaging of cellular and subcellular structures, 3) two-photon multicellular calcium imaging and electrophysiological analysis of hippocampal microcircuits. Although I already possess the skills necessary to implement the first two approaches, I require additional training from my mentor and co-mentor to carry out the circuit- level analysis. Two years of mentored support at the Jan and Dan Duncan Neurological Research Institute at Baylor College of Medicine will allow me to learn these techniques, develop professional skills, and generate additional publications I need to secure a tenure-track faculty position. Successful completion of this project will provide unparalleled insight into the regulation of synaptic and circuit functionby the mTOR signaling network and identify potential targets for treatment of mTOR-related diseases. It will also establish a rigorous framework to test the effects of other neurological disease-causing genes on neuronal function, and an excellent start to a career leading an independent research program.

描述（由申请人提供）：rapamycin （mTOR）信号网络的机制靶点在细胞功能中起着至关重要的作用，整合生长因子、营养可用性和突触输入提供的信息来调节合成等过程