A Role for Glycosphingolipids in Regulatory Mechanisms of Neuron Development

鞘糖脂在神经元发育调节机制中的作用

• 批准号: 7759252
• 负责人: MARJORIE C GONDRE-LEWIS
• 金额: $ 1.84万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759252
• 关键词: Accounting; Area; Behavior; Biogenesis; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cell Nucleus; Cerebral cortex; Characteristics; Cholesterol; Complex; Computer software; Cyclin-Dependent Kinase Inhibitor 3; Data; Defect; Dendrites; Development; Differentiation and Growth; Education; Environment; Event; Faculty; Family member; Foundations; Funding; Gene Expression; Gene Mutation; Genes; Genetic Transcription; Glycosphingolipids; Goals; Growth; Human; Immunofluorescence Microscopy; Knowledge; Lipid IV; Lipids; Maintenance; Membrane; Mentors; Metabolic Brain Diseases; Molecular; Molecular Profiling; Nature; Neuraxis; Neurobiology; Neuroglia; Neurons; Organelles; Pathway interactions; Pilot Projects; Process; Protein Kinase; Protein phosphatase; Proteins; Rattus; Regulation; Repression; Research; Research Proposals; Role; Signal Transduction; Small Interfering RNA; Staging; Steroids; Sterols; Stimulus; Structure; Synapses; Techniques; Testing; Time; Transcript; Universities; Vesicle; Western Blotting; base; calmodulin-dependent protein kinase II; career development; hippocampal pyramidal neuron; immunocytochemistry; lipid metabolism; neuron development; neuronal growth; neurotrophic factor; novel; programs; synaptogenesis; synthetic enzyme; tool; transcription factor

DESCRIPTION (provided by applicant): During development, the cerebral cortex undergoes massive expansion by responding to growth promoting stimuli (GPS) in its environment. These GPS direct neurons to expand lipid-rich membranes adapt vesicular packaging characteristics and extend processes that form long-distance connections. By necessity, induction of glycosphingolipid (GSL) synthesis becomes central in these events, as GSLs modulate neuronal growth, differentiation and signaling. Little is known, however, regarding the mechanisms by which GPS may induce expression of lipid genes. The long-term goal of this research is to establish a mechanistic basis for lipid-dependent control of neuron development, and to introduce novel roles for the growth promoting neurotrophic factor, BDNF, and calmodulin-dependent proteins like the Ca2*lcalmodulindependent protein kinases (CaMKs) in lipid metabolism. Based on our preliminary results, we hypothesize that BDNF, through the abundantly and ubiquitously expressed brain protein, CaMKII, along with other CaMK family members may directly influence lipid synthesis and cargo delivery during neuronal development. We will: 1) Investigate the effects of BDNF on expression and localization of GSLs and their synthetic enzymes. 2) Determine the regulatory relationship between BDNF, CaMKII/IV, lipid expression, and vesicle biogenesis in neurons. 3) Identify lipid related gene transcripts under the control of CaMKII or CaMKIV in cortical pyramidal neurons. The findings generated in this pilot project will provide the foundation for testable hypothesis regarding GPS and GSLs in mechanisms of brain development. This is especially important for understanding developmental brain disorders where metabolic defects in lipid synthesis result from genetic mutations. An important goal of this mechanism is to allow new faculty to develop new research directions and enhance career development in the chosen area. To this end, my planned developmental objectives are to: 1) Initiate a new research program at Howard University, 2) Develop as a competitive PI and mentor in academic research and education, and 3) Acquire funding from a larger R01 style proposal by the 3rd year of the SC2 mechanism in order to maintain a research program with long term funding.

描述（由申请人提供）：在开发过程中，大脑皮层通过响应促进生长刺激（GPS）在其环境中进行大规模扩张。这些GP将神经元直接扩展，以扩展富含脂质的膜，适应囊泡包装特性，并扩展形成长距离连接的过程。必要时，随着GSLS调节神经元的生长，分化和信号传导，在这些事件中诱导糖磷脂（GSL）的合成变得至关重要。然而，关于GP诱导脂质基因表达的机制知之甚少。这项研究的长期目标是为脂质依赖性神经元发育的控制建立机械基础，并引入新作用，以促进神经营养因子，BDNF和钙调蛋白依赖性蛋白（如CA2*Lcalmodultipentent蛋白依赖性蛋白质激酶（CAMKS））在Lipid odid中的作用。基于我们的初步结果，我们假设BDNF通过大量和普遍表达的脑蛋白CaMKII以及其他CAMK家族成员可能直接影响神经元发育过程中的脂质合成和货物递送。我们将：1）研究BDNF对GSL及其合成酶的表达和定位的影响。 2）确定神经元中BDNF，CAMKII/IV，脂质表达和囊泡生物发生之间的调节关系。 3）在皮质锥体神经元中CAMKII或CAMKIV的控制下确定脂质相关的基因转录本。该试点项目中产生的发现将为大脑发育机理中有关GPS和GSL的可检验假设提供基础。这对于理解发育性脑疾病尤其重要，其中脂质合成中的代谢缺陷是基因突变引起的。 该机制的一个重要目标是允许新教师开发新的研究方向并增强所选地区的职业发展。为此，我计划的发展目标是：1）在霍华德大学启动一项新的研究计划，2）发展为学术研究和教育方面的竞争性PI和导师，以及3）3）在SC2机制的第三年之前，从较大的R01风格建议中获得资金，以维持长期资助的研究计划。