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Unveiling CTL1 as the Key Choline Transporter in Oligodendrocytes: Implication for Myelin Formation and Maintenance

Award Number: R21NS140995
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Unveiling CTL1 as the Key Choline Transporter in Oligodendrocytes: Implication for Myelin Formation and Maintenance - Abstract Oligodendrocytes rely heavily on choline to generate myelin membrane, as choline serves as a precursor to essential membrane phospholipids and signaling lipids. Additionally, choline is a source of methyl groups needed for many steps in metabolism and regulation of gene expression. Cells have a limited capacity to synthesize choline; thus, they must acquire it from an extracellular source. Clinical importance of choline intake in myelination has been demonstrated. For instance, prenatal choline deficiency correlates with reduced white matter. Choline supplement has been shown promise in enhancing myelin repair in patience with multiple sclerosis. Despite the recognized significance of choline, we currently have limited understanding of how oligodendrocytes acquire this essential nutrient. The long-term goal of our study is to elucidate the mechanism of choline import and the implications in regulating oligodendrocyte myelination. The expression of choline transporter-like 1 (CTL1) in oligodendrocyte has been reported previously, peaking during active myelination and remaining sustained in adult brain. Since oligodendrocytes do not express CHT, the high-affinity transporter, these observations suggest the role of CTL1 as a choline transporter in oligodendrocytes. Supporting this, a recent human study links non-sense CTL1 mutations to early onset progressive white matter atrophy, highlighting the importance of CTL1 during myelination. The function of CTL1 in oligodendrocytes has not been elucidated. In this study, we aim to test the hypothesis that CTL1 is the main choline transporter in oligodendrocytes and plays a crucial role during oligodendrocyte generation and myelination. Two specific aims are proposed. Aim 1 Do oligodendrocytes acquire choline through CTL1, and what are the implications on myelin lipid synthesis and oligodendrocyte differentiation? We will use MALDI-TOF MS and lipidomic analysis to determine the impact of CTL1 loss on choline import and myelin lipid composition in oligodendrocytes. We will also use scRNA-seq transcriptome analysis to define the impact of CTL1 loss on oligodendrocyte differentiation progression and gene expression Aim 2 Is CTL1 important for oligodendrocyte generation, myelination and myelin maintenance in vivo? Oligodendrocyte lineage-specific PDGFaR-CreER;Ctl1fl/fl;EYFP and PLP-CreER;Ctl1fl/fl;EYFP mice will be used to temporally delete CTL1 in OPCs and mature oligodendrocytes, respectively. Immunohistochemical, biochemical, and ultrastructural EM analyses will assess the impact of CTL1 loss on oligodendrocyte lineage development, myelination, and myelin maintenance. Overall, the study's findings have the potential to significantly advance our understanding of the importance of choline metabolism in myelin biology and provide new insights into developing targeted therapeutic strategies to enhance myelin repair in disorders associated with myelin dysfunction.


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 = $196,250 )
2026	2026	RUTGERS, THE STATE UNIVERSITY	123 WASHINGTON ST	NEWARK	NJ	07102	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/30/2026	NON-COMPETING CONTINUATION	$196,250
														Subtotal = $196,250

Issue Date FY: 2025 ( Subtotal = $235,500 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	123 WASHINGTON ST	NEWARK	NJ	07102	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/26/2024	NEW	$235,500
														Subtotal = $235,500

Grand Total All Awards = $431,750

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Unveiling CTL1 as the Key Choline Transporter in Oligodendrocytes: Implication for Myelin Formation and Maintenance

Award Number: R21NS140995

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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