Entered program in 2010
Sialylation is ubiquitious in mammalian organisms, yet the cellular, genetic and molecular mechanism remain poorly understood due to the pleiotropic effects on the organism as well as the complexity of the sialylation pathway in mammals. Drosophila has a single sialyltransferase, DSiaT, which has been found to play a role in regulating neural transmission by modulating the function of sodium voltage-gated channel PARA that is responsible for the initiation of action potential in neurons. In order to better understand the role of sialylation in the regulation of neural excitability, I will focus on the pathway for the biosynthesis of sialyloglycoconjugates in Drosophila. I will characterize the Drosophila CMP-Sialic acid synthetase (CSAS), the enzyme that mediates the penultimate step in the sialylation pathway and synthesizes the donor sugar for addition by DSiaT. Additional focus of my project will be on the function of sialylation in membrane excitability and investigating a putative target of DSiaT activity, the sodium voltage-gated channel PARA. Currently the genetic and molecular mechanisms of sialylation remain unresolved. This work will contribute to our knowledge of the role of sialylation in regulating neural transmission and uncover potentially conserved mechanisms between Drosophila and mammals.
Broader Impacts of Research Project:
My research focuses on glycosylation, which is the most prolific post-translational modification. It is likely that every protein has a sugar attached. These sugars, or glycans, are involved in the immune system, neural development, cell signaling and host pathogen interactions. While defects in the pathway itself lead to a range of disorders such as Congenital Disorders in Glycosylation (CDG), defects in glycosylation have been linked to immune disorders, cancer, and heart disease. Sialylation,a type of glycolsylation, is prohibitively complex in mammalian model organisms. Our lab discovered a evolutionarily conserved sialyltranferase in Drosophila, indicating that sialylation is present in proteomes establishing Drosophila as a model organism in the study of the genetics and function of sialylation. Previous work in our lab points to sialylation as being necessary for normal neural development and transmission. It is important to understand the mechanisms of sialylation-mediated excitability in order to gain greater understanding into the role of sialylation in neural transmission. Drosophila sialyltransferase was shown to regulate the function of a sodium voltage-gated channel protein in Drosophila, and is closely related to the major excitability channel in humans (SCN5A). Defects in this channel lead to a wide range of channelopathies including LQT syndrome, Brugada Syndrome as well as arrhythmias and heart failure. This research will lead to a greater understanding of the genetic and functions mechanisms of sialylation that are conserved in humans leading to new approaches in therapeutics in neurological disorders, and heart disease and cancer.