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Defining the Disease-Causing HRasG12V Mutation as a Link for Defective Myelin and Subnormal Learning

Award Number: K01NS126813
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Defining the Disease-Causing HRasG12V Mutation as a Link for Defective Myelin and Subnormal Learning - PROJECT SUMMARY/ABSTRACT Formation, maintenance, and/or modification of myelin is necessary for high order brain functions including learning, but it is still unclear whether myelin defects contribute to the onset of neurological conditions including Learning Disabilities (LD), Attention Deficit and Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders (ASD). As genetic factors are believed to contribute to the onset of these conditions, the overall goal of this study is to define molecular links for defective myelin/myelination and subnormal learning and memory in a monogenic disease. Two myelin-centered mouse models of Costello Syndrome (CS) will be used as: CS is caused by mu- tations in a single gene (HRas); CS patients present with high predisposition to develop LD, ADHD, and ASD in correlation with abnormal myelin and White Matter (WM); and CS mouse models mimic diverse patient pheno- types. To test the hypothesis that a CS mutation impairs motor skill learning by disturbing the function and the timely/accurate formation of myelin, HRasG12V mutation will be induced in Oligodendrocytes (OLs; myelin pro- ducing cells) and OL Precursor Cells (OPCs) at strategic time points. Preliminary results support that HRasG12V in pre-existing OLs impairs learning of fine motor skills. Hence, Aim1 involves defining cell-autonomous/non-cell- autonomous mechanisms regulating this learning phenotype, particularly those linked to increased nitric oxide (NO) signaling. The Aim 2 will define changes in basal and learning-induced myelination, and functional connec- tivity upon HRas mutation in OPCs of the developing and adult brain. This study is original and innovative as it can impact our general understanding of brain function/dysfunction; it will be first in establishing developmental and chronic roles of HRas as the link for defective myelin and subnormal learning. Drugs studied used here - targeting glial NO - can diversify and expedite the development of treatments for CS and associated conditions. Finally, experimental evidence obtained will help settle the long-lasting debate on the links between abnormal myelin and the neuropathophysiology of RAS/MAPK pathway-related diseases (RASopathies). The PI’s expertise is in in vivo glial pathways and behavioral analyses and has been productive in RASopathy research. To establish a solid research program and become competitive for NIH R01 funding, training goals include attaining expertise in myelin biology, learning brain-wide research approaches (fcMRI, high-volume brain imaging), and acquiring a clinical perspective of RASopathies. Therefore, the mentoring team includes 1) a pio- neer scientist in myelin biology (~30 years in the field), 2) an expert/innovator in rodent MRI brain analyzes, 3) a leading clinician in RASopathies, and 4) a prosperous intramural scientist to guide the PI’s tenure promotion. The planned research and training were designed to promote the PI’s independence and to be foundation for an R01 application aimed toward defining myelin-regulated behaviors upon germline HRas mutation. Additionally, obtaining collaborations and preliminary data for electrophysiological analyses, behavioral tests of ADHD and ASD, and transcriptional and epigenomic analysis, among others, are scheduled in the period of support.


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: 2026 ( Subtotal = $210,312 )
2026	2026	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/5/2026	NON-COMPETING CONTINUATION	$210,312
														Subtotal = $210,312

Issue Date FY: 2025 ( Subtotal = $210,312 )
2025	2025	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/13/2025	NON-COMPETING CONTINUATION	$210,312
														Subtotal = $210,312

Issue Date FY: 2024 ( Subtotal = $210,312 )
2024	2024	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/28/2024	NON-COMPETING CONTINUATION	$210,312
2024	2023	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $210,312

Issue Date FY: 2023 ( Subtotal = $210,312 )
2023	2023	UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/13/2023	NON-COMPETING CONTINUATION	$210,312
														Subtotal = $210,312

Issue Date FY: 2022 ( Subtotal = $210,312 )
2022	2022	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/1/2022	NEW	$210,312
														Subtotal = $210,312

Grand Total All Awards = $1,051,560

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Defining the Disease-Causing HRasG12V Mutation as a Link for Defective Myelin and Subnormal Learning

Award Number: K01NS126813

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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