Wednesday, February 18, 2026 2/18/2026

Function of ALKBH8 and tRNA modification in the nervous system

Award Number: R01NS117068
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Function of ALKBH8 and tRNA modification in the nervous system - PROJECT SUMMARY/ABSTRACT Nervous system development and function demands tight regulation of gene expression. Post-transcriptional modification of RNA regulates gene expression at multiple levels and tRNA modifying enzymes are emerging as important regulators of nervous system development and function. Here, we build on our in vivo studies of ALKBH8 in Drosophila. ALKBH8 is a wobble uridine tRNA methyltransferase recently identified as the causative gene for intellectual disability in a growing number of families. Our findings support the model that ALKBH8-dependent methylation of tRNA-Sec promotes selenoprotein synthesis and the regulation of oxidative stress to restrain synapse formation and promote learning and memory. In Aim 1, we build on these findings to determine the contribution of selenoproteins to memory deficits in ALKBH8 null animals and investigate approaches for circumventing ALKBH8-dependent tRNA-Sec methylation in the nervous system. We will also leverage whole brain transcriptomic and proteomic datasets we have generated to identify additional ALKBH8- dependent proteins. In Aim 2, we define the spatio-temporal requirements for ALKBH8 in nervous system development and function and characterize the dynamic regulation of ALKBH8-dependent tRNA modifications during neurodevelopment and in response to neuronal activity or oxidative stress. In Aim 3, we expand our investigations to complementary human iPSC-derived neurons and brain organoids to understand the impact of intellectual-disability associated variants. Through this integrative approach we will gain deep mechanistic understanding of ALKBH’s role in nervous system development and function and how it goes awry in disease states while identifying critical windows and targets for therapeutic intervention. More broadly, our studies will reveal fundamental insights into the critical, yet understudied, role of tRNA modification in the dynamic regulation of gene expression in the nervous system.


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 = $478,722 )
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/6/2026	COMPETING CONTINUATION	$478,722
2026	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $478,722

Issue Date FY: 2024 ( Subtotal = $359,422 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/8/2024	NON-COMPETING CONTINUATION	$25,939
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/23/2024	NON-COMPETING CONTINUATION	$333,483
														Subtotal = $359,422

Issue Date FY: 2023 ( Subtotal = $370,496 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/28/2023	NON-COMPETING CONTINUATION	$370,496
														Subtotal = $370,496

Issue Date FY: 2022 ( Subtotal = $370,842 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/25/2022	NON-COMPETING CONTINUATION	$370,842
														Subtotal = $370,842

Issue Date FY: 2021 ( Subtotal = $371,124 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/11/2021	NON-COMPETING CONTINUATION	$371,124
														Subtotal = $371,124

Issue Date FY: 2020 ( Subtotal = $385,730 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/28/2020	NEW	$385,730
														Subtotal = $385,730

Grand Total All Awards = $2,336,336

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Function of ALKBH8 and tRNA modification in the nervous system

Award Number: R01NS117068

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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