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Mechanisms of neuronal TRPM2 channel effects on Post-Stroke Cognitive Impairment

Award Number: F31NS145622
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2025
PERIOD OF PERFORMANCE END DATE: 09/29/2028

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Mechanisms of neuronal TRPM2 channel effects on Post-Stroke Cognitive Impairment - Abstract / Project Summary Stroke is a significant contributor to death and disability worldwide. With increased survivability due to advancements in clinical treatments, 35-50% of patients suffer from long-term neurological deficits in learning and memory termed Post-Stroke Cognitive Impairment (PSCI). Utilizing the middle cerebral artery occlusion (MCAO) model of focal ischemia, we can investigate chronic timepoints post-stroke to ameliorate cognitive deficits. Our lab has targeted the transient receptor potential melastatin 2 (TRPM2) channel as a potential locus of therapeutics. As a Ca2+ permeable non-specific cation channel, TRPM2 is activated in periods of oxidative stress, such as in stroke, and contributes to both cognitive and synaptic dysfunction. Indeed, data obtained in the laboratory before I joined demonstrates that acute and delayed administration of a TRPM2 channel antagonist improves synaptic and cognitive recovery following experimental stroke. TRPM2 is in multiple cell- types throughout the brain, and I seek to investigate the neuronal component of TRPM2 by utilizing genetic animal models and adeno-associated viruses (AAVs) to conditionally knockout TRPM2 from neurons. In aim 1, I hypothesize that a neuron-specific knockout rescues long-term potentiation (LTP) and behavioral deficits up to 30-days post-stroke. In aim 2, I seek to investigate the downstream mediators of TRPM2. Data suggests that in periods of hypoxia, a positive feedback loop is initiated; TRPM2 is activated and the kinase PKC is then recruited to the area where it phosphorylates TRPM2 at serine 38 further enhancing activation of the TRPM2 channel. Calcineurin activates (dephosphorylates) glycogen synthase kinase 3-beta (GSK-3) after TRPM2 activation. Evidence shows that dephosphorylated GSK-3 is responsible for the internalization of a-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors ultimately leading to a decrease in LTP. A final player in this complex signaling pathway is regulator of calcineurin 1 (RCAN1), which binds to calcineurin and increases its activity at key phosphorylation sites. Due to RCAN1’s role within the calcineurin-GSK-3β signaling pathway, RCAN1 is implicated in the bidirectional regulation of hippocampal synaptic plasticity. Data further suggests a potential link between PKC and the downstream actions of RCAN1 are mediated by TRPM2 channel activation. In aim 2, I hypothesize that decreasing RCAN1 and GSK-3 expression will rescue LTP deficits. This training plan will build methodological skills in electrophysiology, biochemical analyses, and more culminating in multiple manuscripts. It will also foster the growth of my career attending seminars focused on women in STEM, networking to further the advancement of women throughout academia, and mentoring the next generation of scientists. I have chosen Dr. Paco Herson as my mentor at The Ohio State University because they maintain incredibly high standards in state-of-the-art facilities that will ensure my development as an academic neuroscientist.


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 = $44,916 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/30/2025	NEW	$44,916
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/30/2025	NEW	$0
														Subtotal = $44,916

Grand Total All Awards = $44,916

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Mechanisms of neuronal TRPM2 channel effects on Post-Stroke Cognitive Impairment

Award Number: F31NS145622

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2025

PERIOD OF PERFORMANCE END DATE: 09/29/2028

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