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Organellar Na+/H+ Exchangers and Intracellular pH Regulation in Schizophrenia Brain

Award Number: K23MH127303
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $191,376 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	4	1/22/2025	NON-COMPETING CONTINUATION	$191,376
														Subtotal = $191,376

Issue Date FY: 2024 ( Subtotal = $191,376 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	3	12/8/2023	NON-COMPETING CONTINUATION	$191,376
														Subtotal = $191,376

Issue Date FY: 2023 ( Subtotal = $191,376 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	2	12/5/2022	NON-COMPETING CONTINUATION	$191,376
														Subtotal = $191,376

Issue Date FY: 2022 ( Subtotal = $191,376 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	1	2/1/2022	NEW	$191,376
														Subtotal = $191,376

Grand Total All Awards = $765,504

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Organellar Na+/H+ Exchangers and Intracellular pH Regulation in Schizophrenia Brain

Award Number: K23MH127303

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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