A Role for Glycosphingolipids in Regulatory Mechanisms of Neuron Development

描述(申请人提供)：在发育过程中，大脑皮层通过对其环境中的生长促进刺激(GPS)做出反应而经历大规模扩张。这些GPS引导神经元扩展富含脂质的膜，适应囊泡包装特征，并延长形成长距离连接的过程。不可避免地，神经鞘糖脂(GSL)合成的诱导在这些事件中成为中心，因为GSL调节神经元的生长、分化和信号传递。然而，关于GPS诱导脂肪基因表达的机制还知之甚少。本研究的长期目标是建立脂质依赖控制神经元发育的机制基础，并引入促生长神经营养因子和钙调素依赖蛋白如钙调素依赖性蛋白激酶(CaMKs)在脂质代谢中的新作用。根据我们的初步结果，我们推测BDNF可能通过丰富而普遍表达的脑蛋白CaMKII和其他CaMK家族成员直接影响神经元发育过程中的脂质合成和货物运输。我们将：1)研究BDNF对GSLS及其合成酶表达和定位的影响。2)确定BDNF、CaMKII/IV、脂质表达与神经元囊泡生物发生的调控关系。3)鉴定皮质锥体神经元中CaMKII或CaMKIV调控下的脂质相关基因转录本。这个试点项目中产生的结果将为关于GPS和GSLS在脑发育机制中的可验证性假说提供基础。这对于理解发育性大脑疾病尤其重要，在这些疾病中，脂肪合成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的教员在选定的领域发展新的研究方向和促进职业发展。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)发展成为学术研究和教育领域具有竞争力的PI和导师，3)在SC2机制的第三年从更大的R01风格的提案中获得资金，以维持一个长期资助的研究项目。

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.