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Transcriptional regulation of mitochondrial metabolism in human intestinal stem cells

Award Number: K01DK140610
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Transcriptional regulation of mitochondrial metabolism in human intestinal stem cells - PROJECT SUMMARY Joseph Burclaff, PhD is opening a lab at North Carolina State University (NCSU), mentored by Michele Battle, PhD following a research professorship at UNC Chapel Hill. NCSU is a member of the NIDDK-sponsored Center for Gastrointestinal Biology and Disease (CGIBD) alongside UNC, with a vibrant community of researchers. The CGIBD and Dr. Burclaff’s home department of Molecular Biomedical Sciences provide supportive environments for young investigators. Dr. Burclaff proposes an innovative cross-disciplinary research plan bridging human tissue culture and genetic engineering, mouse work, metabolomics and functional metabolic studies, and transcription factor analysis studying homeostasis and inflammatory bowel disease (IBD). Dynamic regulation of mitochondrial metabolism is essential for healthy intestinal stem cell (ISC) activity, with mitochondrial dysfunction leading to aberrant proliferation and cell fate and sufficient to initiate experimental colitis. Decreased mitochondrial levels and activity and pro-inflammatory gene expression are seen in early IBD and even in non-inflamed tissue from IBD patients, implicating these changes as some of the earliest events in IBD development, possibly even predisposing the intestinal epithelium for inflammation. Few transcription factors (TFs) are shown to regulate mitochondrial dynamics in ISCs. My work with primary human ISCs genetically engineered to knockout or inducibly overexpress the TF SOX9 show that SOX9 strongly represses mitochondrial activity in ISCs without strongly affecting levels of previously implicated TFs. This suggests that SOX9 regulates mitochondria independently of known transcriptional networks. This proposal will determine how SOX9 regulates mitochondria and pro-inflammatory genes in human ISCs and in the mouse intestine (Aim 1). As SOX9 often acts through other TFs, candidate TFs identified using this primary human ISC platform will be tested for their ability to regulate mitochondria independently or as a TF network. Cutting-edge cellular engineering strategies will further identify and test direct downstream targets of these TFs to determine mechanisms by which this novel network regulates mitochondria and pro-inflammatory gene expression in the intestinal epithelium. To ensure the success of the proposed research and to establish an independent research area in this field, Dr. Burclaff requires additional mentored time to become fluent in metabolism and metabolomics, TF interactions and direct study of downstream genomic targets, and studying inflammatory diseases. To achieve this, Dr. Burclaff will be co-mentored by Dr. Costas Lyssiotis at the University of Michigan, a field expert in metabolism and metabolomic analysis in gastrointestinal tissues and disease states. Dr. Burclaff also assembled a committee of field experts in metabolism, chromatin and TF analysis, and IBD to help guide him through this project and in his transition to establish an independent research program to train the next generation of researchers and to study regulatory mechanisms of ISCs that affect human health.


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 = $222,150 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/4/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$108,362
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/21/2026	NON-COMPETING CONTINUATION	$0
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/19/2026	NON-COMPETING CONTINUATION	$113,788
														Subtotal = $222,150

Issue Date FY: 2025 ( Subtotal = $115,288 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/2/2025	NEW	$115,288
														Subtotal = $115,288

Grand Total All Awards = $337,438

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Transcriptional regulation of mitochondrial metabolism in human intestinal stem cells

Award Number: K01DK140610

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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