Retrograde Regulation of Synaptic Strength by Translational Mechanisms

翻译机制对突触强度的逆行调节

• 批准号: 8596748
• 负责人: Ali Pejmun Haghighi
• 金额: $ 42.44万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596748
• 关键词: 5' Untranslated Regions; Affect; Back; Binding Proteins; Biochemistry; Biological Assay; Cap Binding Protein Complex; Cells; Communications Media; Complex; Cues; Data; Dietary intake; Disease; Drosophila genus; Electrophysiology (science); Ensure; Equilibrium; Eukaryotic Initiation Factor-4E; Feedback; Feeds; Financial compensation; Fractionation; Future; Generations; Genes; Genetic; Glutamate Receptor; Growth; Homeostasis; Human; Image; Intake; Larva; Life; Life Cycle Stages; Light; Link; Maintenance; Messenger RNA; Modeling; Molecular; Molecular Biology; Motor Neurons; Muscle; Mutation; Nature; Nerve; Nervous system structure; Neuromuscular Junction; Neurons; Neurotransmitters; Normal Range; Nutritional; Organism; Parkinson Disease; Phosphorylation; Phosphotransferases; Physiological; Polyribosomes; Process; Protein Biosynthesis; Publishing; Regulation; Research; Research Design; Ribosomal Protein S6 Kinase; Role; Signal Transduction; Signaling Molecule; Sirolimus; Structure; Study models; Synapses; Synaptic Transmission; Therapeutic; Time; Translating; Translations; Work; base; design; dietary restriction; extracellular; fly; insight; interdisciplinary approach; interest; mutant; nervous system disorder; neural circuit; neurotransmitter release; nutrition; overexpression; postsynaptic; presynaptic; programs; public health relevance; receptor; relating to nervous system; research study; response; synaptic function

DESCRIPTION (provided by applicant): Appropriate regulation of synaptic strength is essential for maintaining stability in neural circuits. This regulation hinges on a balance between molecular mechanisms that promote change in synaptic function in response to extracellular and intracellular cues, and homeostatic mechanisms that seek to adjust neuronal function within a normal range, ensuring stability in neural circuits circuits1-2. This proposal is designed to unravel molecular components and mechanisms that contribute to homeostatic mechanisms at the synapse. My group has been taking advantage of the Drosophila larval neuromuscular junction (NMJ) as a model synapse. When postsynaptic function is reduced at this synapse, a robust homeostatic retrograde signal is initiated in the postsynaptic muscles, which feeds back to the presynaptic motor neuron to cause a compensatory enhancement in presynaptic neurotransmitter release1. The NMJ is a particularly well-suited model for studying this feedback or retrograde signaling mechanism, since the short life cycle of flies together with the powerful genetics available in Drosophila allow for an efficient identification and characterizatio of genes and mechanisms that participate in this coordinated process. In particular, our recently published work3 as well a wealth of unpublished preliminary findings indicate that translational mechanism that control do novo protein synthesis are essential for the ability of the NMJ to induce this retrograde compensation in neurotransmitter release. In addition, we have strong preliminary data that a Parkinson's related genes interacts with translational mechanisms and thereby influences synaptic transmission at the NMJ. We have also identified potential translational targets for postsynaptic translation that may further shed light into the nature of tis signaling. Our research plan is based on a wealth of preliminary data and unpublished observations and utilizes a multidisciplinary approach that combines Drosophila genetics with molecular biology, biochemistry, imaging and electrophysiology. We have a unique opportunity for understanding how retrograde signaling operates at synapses to induce homeostatic effects. In light of the highly conserved nature of these signaling molecules, our findings hold the promise of being translated to higher organisms and pave the way for future therapeutic approaches aimed at tackling nervous system diseases.

描述（由申请人提供）：适当调节突触强度对于维持神经回路的稳定性至关重要。这一规定取决于两者之间的平衡