LKB1 function in axon development through regulation of mitochondrial trafficking

LKB1 通过调节线粒体运输在轴突发育中发挥作用

• 批准号: 8502190
• 负责人: Tommy L Lewis
• 金额: $ 1.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502190
• 关键词: Affect; Alzheimer' s Disease; Axon; Axonal Transport; Biochemical; Biological Assay; Cell Death; Cells; Co-Immunoprecipitations; Defect; Development; Dynein ATPase; Electroporation; Endosomes; Genetic; Goals; Heart; Huntington Disease; In Vitro; Kinesin; Knock-out; Knowledge; Lead; Link; Maintenance; Mediating; Microscopy; Mitochondria; Molecular; Nervous system structure; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Preparation; Presynaptic Terminals; Property; Proteins; Regulation; Research; STK11 gene; Surface; Synapses; Testing; Time; Venus; Vesicle; Work; anterograde transport; axon growth; cell motility; in utero; in vivo; insight; loss of function; neuron development; polarized cell; presynaptic; research study; retrograde transport; syntaphilin; time use; trafficking

DESCRIPTION (provided by applicant): The development and maintenance of polarity is paramount to neuronal development and function. The loss of this cell state is realized in many neurodegenerative diseases and ultimately leads to cell death. This project will lead to a greater understanding of the mechanisms responsible for polarization and its maintenance. The goal of this project is to characterize the contribution that the recently discovered LKB1 kinase pathway plays in axon growth and branching through polarized transport of cargo. Specific Aim 1 will provide the necessary framework for understanding how LKB1 and NUAK1/2 affect the transport of mitochondria in the axon. Specific Aim 2 will characterize the mechanism by which transport is regulated by determining the downstream components of the kinase pathway. The interaction between LKB1/NUAK and the mitochondrial anchor protein syntaphilin will be the main focus of this aim. Specific Aim 3 will then attempt to link mitochondrial transport in the axon to proper axon branching and projection within layer 2/3 neurons of the cortex. This research will provide important new knowledge that will be useful in understanding the basic mechanisms at work in many neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's.

描述（由申请人提供）：极性的发展和维护对于神经元发展和功能至关重要。在许多神经退行性疾病中，这种细胞状态的丧失已实现，并最终导致细胞死亡。该项目将对负责两极分化及其维护的机制有更深入的了解。该项目的目的是表征最近发现的LKB1激酶途径在轴突生长中通过货物的极化运输在分支中发挥作用的贡献。具体目标1将提供必要的框架，以了解LKB1和NUAK1/2如何影响轴突中线粒体的运输。特定的目标2将通过确定激酶途径的下游成分来调节传输的机制。 LKB1/NUAK与线粒体锚蛋白杂种蛋白之间的相互作用将是该目标的主要重点。然后，特定的目标3将尝试将轴突中的线粒体转运与皮质的2/3层神经元内的适当轴突分支和投影联系起来。这项研究将提供重要的新知识，这些知识将有助于理解许多神经退行性疾病的基本机制，包括阿尔茨海默氏症，亨廷顿和帕金森氏症。