Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Identifying molecular mechanisms contributing to disease etiology and the neurological symptoms associated with pediatric DPD deficiency

Award Number: F31NS141217
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: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

Group Awards By:

View Award Description

Identifying molecular mechanisms contributing to disease etiology and the neurological symptoms associated with pediatric DPD deficiency - PROJECT SUMMARY Dihydropyrimidine dehydrogenase (DPD) deficiency, caused by mutations within DPYD, has been studied mostly in the context of 5-fluorouracil (5-FU) toxicity and its role as a pharmacogene. However, a rare pediatric disorder with severe early onset symptoms, pediatric DPD deficiency, is also linked to genetic variation within DPYD. The molecular mechanisms that contribute to disease onset and associated symptoms are unknown, nor have any effective therapeutic avenues been identified, likely owing to the lack of mechanistic knowledge. Therefore, in the proposed studies, I will use induced pluripotent stem cell (iPSC)- derived cerebral organoid models of pediatric DPD deficiency to identify the mechanisms linking DPD deficiency with the outward symptoms of the condition. The overall goals of the proposed studies are to define disease etiology, determine molecular mechanisms that lead to disease onset, and to identify potential therapeutic targets. We hypothesize that dysregulation of excitatory and inhibitory signaling within the brain contributes to seizure onset and epilepsy due to excitotoxicity and a decrease in β-alanine inhibitory signaling, along with anatomical structural changes across development and differences in cellular composition. We further hypothesize that the symptoms of this disorder could be relieved by correcting genetic variation within DPYD. To address this hypothesis, we will identify differentially expressed genes and dysregulated pathways at bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels to determine molecular mechanisms contributing to the disease. We will investigate the potential for dysregulation of gene expression via epigenetic mechanisms and perform functional studies of organoid signaling. Finally, isogenic cell line models will be established to determine if the molecular and functional phenotype of organoids derived from affected patients is specifically dependent on DPYD genetic variation. Overall, these data will describe the etiology of pediatric DPD deficiency, determine molecular mechanisms and pathways contributing to symptom onset, and aid in therapeutic target identification for disease treatment. These studies will provide broad implications into the role of DPYD in neurological development and developmental mechanisms contributing to pediatric genetic epilepsy onset.


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 = $50,114 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/11/2026	NON-COMPETING CONTINUATION	$49,538
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	3/31/2026	NON-COMPETING CONTINUATION	$576
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/10/2026	NEW	$0
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/28/2025	NEW	$48,974
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/9/2025	NEW	$564
														Subtotal = $49,538

Grand Total All Awards = $99,652

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Identifying molecular mechanisms contributing to disease etiology and the neurological symptoms associated with pediatric DPD deficiency

Award Number: F31NS141217

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: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer