Raghu Padinjat's lab
Research
Model systems
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We use two model systems for our work (i) Drosophila photoreceptors where we study multiple aspects of PI signaling in the control of sub-cellular organization and and PLC based signal transduction. The goal is to discover key principles of signal transduction that are likely to be conserved during evolution but are experimentally more tractable in Drosophila. It is hoped that in the medium term, our analysis in Drosophila will inform studies of equivalent signaling pathways in mammalian models with more immediate biomedical relevance. (ii) Human disease models of brain disorders where we use a combination of human genetics and induced pluripotent stem cell (hiPSC) technology to uncover the cell biology of human brain development and function and its regulation by PIs.
Regulation of PI(4,5)P2 signaling in neural cells
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Neural cell use phospholipase C (PLC) activation and the hydrolysis of PI(4,5)P2 as a key signaling mechanism to encode information transfer. Many G-protein couple receptors important for brain development an (e.g. metabotropic glutamate receptors) use PLC mediated signaling for key processes such as learning and memory. The final output of this pathway, calcium influx is key to encode many types of information in neurons. We are interested in understanding the control of PI(4,5)P2 turnover following PLC activation. For this we use Drosophila photoreceptors as a model system (Yadav et.al). A related interest is the mechanism of action of Li, a key-mood stabilization therapy used in the treatment of bipolar disorder in human patients. The mechanism by which Li acts on the brain remains unclear. We are working on the mechanism of action of Li using a combination of human genetics, biochemistry and gene editing technologies using human iPSC derived “disease in a dish“ models of human brain cells.
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Sub-cellular organization in neurons
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Rapid signaling is critical to neuronal function and given these are large cells localization and compartmentalization of molecules and biochemical reactions is key to achieving speed and specificity. In the context if lipid molecules, this requires the rapid transfer of lipid signaling intermediates between cellular organelles. This is thought to occur via membrane contact sites, sites within cells where two organelle membranes come in close proximity without fusing. We study the regulation of contact site structure and function using Drosophila photoreceptors where lipid transfer between the plasma membrane and endoplasmic reticulum is essential for supporting PI(4,5)P2 turnover during PLC signaling. The work is done using a combination of lipid biochemistry, molecular genetics, electron microscopy and in vivo imaging.
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Regulation of membrane trafficking by phosphoinositides
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In addition to their role in supporting receptor mediated signaling, phosphoinositides are key regulators of membrane trafficking and cellular organization. We study this problem using both Drosophila photoreceptors and iPSC derived neural models in culture. The function of phosphatidylinositol 5 phosphate 4-kinase its substrate PI5P and product PI(4,5)P2 is being studied using both the Drosophila model as well as the human genetic disorder Lowes syndrome where patients harbor mutations in the PI(4,5)P2 5-phosphatase OCRL. We are also studying the functions of PIP4K in regulating membrane transport.
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