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Role of hypothalamic IRF3 transcriptional dysregulation in obesity

Award Number: K01DK131347
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Role of hypothalamic IRF3 transcriptional dysregulation in obesity - Abstract Arriving at a more granular understanding of the molecular drivers of appetite will represent a major step towards the ultimate goal of more efficiently treating obesity. AgRP neurons in the arcuate nucleus (ARC) of the hypothalamus play a dominant role in maintaining energy balance and are dysregulated in obesity. We have recently utilized cutting-edge tools to enable an unprecedented cell type-specific characterization of the transcriptional and epigenomic landscape of AgRP neurons, and this information was leveraged to identify one transcription factor, Interferon Regulatory Factor 3 (IRF3) that mediates the acute anorectic effects of leptin. The current project seeks to examine the role of AgRP neuron IRF3 (IRF3AgRP) in the development of diet- induced obesity (DIO) involving loss- and gain-of-function experiments while assessing the impact on mouse body weight, feeding behavior, and leptin sensitivity. The transcriptomic profiles of these IRF3 functional mouse models will be examined in the lean state in response to leptin, and in the obese state. Additionally, the direct DNA binding targets of IRF3AgRP will be elucidated using a cutting-edge, low-input, alternative to ChIP- seq called CUT&RUN, all in the lean fed, fasted, and leptin treated state, and in response to obesity. AgRP neuron-specific ATAC-seq for lean and obese AgRP neuronal nuclei will also be performed as a means of assessing the transcriptional regulatory status of IRF3 and other TFs during obesity. Finally, using both lean and obese mice that are either wild-type or have IRF3 knockout out of all leptin-receptor expressing cells, I will perform single nucleus RNA-seq as a means of identifying the IRF3-driven transcriptional programs onboard in the obese state. Overall, these studies will test the overarching hypothesis that IRF3 plays key roles in mediating both acute leptin sensitivity as well as the development of diet-induced obesity owed to chronic IRF3 activation via hyperleptinemia. The regulatory pathways highlighted in this project will point to novel therapeutic targets for the treatment of obesity, a major risk factor for type 2 diabetes. During the course of the mentored phase of this application, I will further strengthen the computational skills needed to analyze RNA-seq, ATAC- seq, CUT&RUN, and single-nucleus RNA-seq datasets independently. I will also engage in various career development experiences, while also receiving invaluable mentorship from my career advisory committee. In all, the funding of the proposed project will ensure that I round out my scientific and professional training while laying the foundation for a viable independent academic research program.


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: 2025 ( Subtotal = $150,736 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/5/2025	NON-COMPETING CONTINUATION	$150,736
														Subtotal = $150,736

Issue Date FY: 2024 ( Subtotal = $150,736 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/9/2024	NON-COMPETING CONTINUATION	$150,736
2024	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,736
2024	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/14/2024	NEW	-$150,736
														Subtotal = $150,736

Issue Date FY: 2023 ( Subtotal = $150,736 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/25/2023	NEW	$150,736
														Subtotal = $150,736

Grand Total All Awards = $452,208

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Role of hypothalamic IRF3 transcriptional dysregulation in obesity

Award Number: K01DK131347

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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