A Role for Glycosphingolipids in Regulatory Mechanisms of Neuron Development

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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.