A Role for Glycosphingolipids in Regulatory Mechanisms of Neuron Development

描述（由申请人提供）：在发育过程中，大脑皮层通过响应其环境中的生长促进刺激（GPS）而经历大规模扩张。这些GPS指导神经元扩展富含脂质的膜，适应囊泡包装特性，并扩展形成长距离连接的过程。由于鞘糖脂（GSL）调节神经元的生长、分化和信号传导，因此鞘糖脂（GSL）合成的诱导必然成为这些事件的核心。然而，关于GPS可能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建立一个机制的基础上，脂质依赖性控制神经元发育，并介绍新的作用，促进生长的神经营养因子，BDNF，钙调素依赖性蛋白质，如钙2 * 1钙调素不依赖性蛋白激酶（CaMK）在脂质代谢。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，CaMK II，沿着与其他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输送。1）研究BDNF对GSL及其合成酶表达和定位的影响。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)鉴定皮质锥体神经元中受CaMKII或CaMKIV控制的脂质相关基因转录本。本研究的结果将为GPS和GSL在脑发育机制中的可验证假设提供基础。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由基因突变引起的。 这一机制的一个重要目标是允许新教师开发新的研究方向，并加强在所选领域的职业发展。为此，我计划的发展目标是：1）在霍华德大学启动一个新的研究项目，2）发展成为一个有竞争力的PI和导师在学术研究和教育，和3）获得资金从一个更大的R 01风格的建议，由第三年的SC 2机制，以保持一个长期的研究计划的资金。

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.