Wednesday, April 23, 2025
4/23/2025
Organellar Na+/H+ Exchangers and Intracellular pH Regulation in Schizophrenia Brain - Candidate: I am an Assistant Professor in UAB’s Department of Psychiatry with a background in molecular methods used in preclinical models and the role of intracellular pH dysregulation in neurodevelopmental illnesses. Additionally, I have expertise in diagnosis and treatment of psychopathology having received my MD- PhD from LSU Health Shreveport and completed a Psyhciatry Residency at Brown University. Career Goals and Development: I hope to gain expertise in assessing schizophrenia (SZ)-associated molecular disruptions in postmortem brain, in generating SZ patient-derived induced pluripotent stem cells (iPSCs) and differentiating them into disease relevant cell types, and in measuring cellular trafficking and luminal pH through the use of fluorescently-tagged protein constructs. By acquiring these skills and completing the studies laid out in this proposal, I will be well positioned and competitive for independent funding. Research Project: Deficits in protein post-translational modifications (PTM) and trafficking are reported in schizophrenia (SZ) brain, but the underlying cause is unknown. The function of organelles involved in PTM and trafficking is greatly impacted by pH disruptions, and Na+/H+ Exchangers (NHE) 6-9 are major regulators of organelle pH. In cancer cells, hypoxia causes altered energy metabolism and redistribution of NHE6 from endosomes to the plasma membrane. Similar metabolic alterations are reported in SZ brain suggesting that NHE6-9 intracellular distribution may also be affected, which could contribute to disrupted protein PTM and trafficking. So far, I have found that NHE7/8 expression is decreased in SZ dorsolateral prefrontal cortex (DLPFC) while NHE6/9 is unchanged. Still, NHE6/9 show increased expression in a tissue fraction enriched for synapses suggesting altered distribution of these proteins. Here, I propose to more extensively determine the expression and distribution of NHE6-9 first in SZ postmortem DLPFC and then in excitatory cortical neurons and astrocytes differentiated from patient-derived iPSCs. I will also determine how the introduction and removal of an acute stressor (hypoxia) affects the distribution of these proteins in these cells. Finally, I will transfect cells with fluorescently-tagged protein constructs to measure NHE6-9 and neurotransmitter receptor trafficking as well as organelle pH in live cells. These studies could help identify novel treatment targets for SZ and lead to high throughput assays to identify drugs that reverse SZ-associated molecular disruptions. Mentorship: The primary mentorship team for this proposal consists of Dr. James Meador-Woodruff, a world renowned expert in molecular disruptions in schizophrenia brain and analysis of postmortem brain tissue, Dr. Marek Napierala, an expert on molecular mechanisms of repeat expansion disorders and of modeling these illnesses using iPSCs differentiated into a variety of cell types including cortical neurons, and Dr. Vladimir Parpura, an expert in glial biology and visualization of vesicular trafficking in live cells through the use of fluorescently-tagged protein constructs.
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