Thursday, November 21, 2024 11/21/2024

Role of intestinal luminal and epigenetic factors to mediate intestinal metabolic remodeling after gastric bypass surgery

Award Number: K08DK125878
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT SUMMARY The rising incidence of type 2 diabetes (T2D) highlights a growing need to understand mechanisms behind highly-effective therapies such as Roux-en-Y gastric bypass surgery (RYGB) in order to develop better, more widely-applicable treatments. The long-term goal is to understand the role of luminal factors to mediate the effect of intestinal re-routing upon energy metabolism, including T2D. The overall objective of this application is to test for tissue-level epigenetic changes in the intestine after RYGB, as a potential mechanism for Roux limb (RL) remodeling that we have shown to relate to T2D remission in humans. The central hypothesis is that RL metabolic reprogramming is driven by segment-specific epigenetic modifications which are plastic and require continuous luminal stimulation. The rationale for this project is that a greater understanding of intestinal gene expression regulatory networks after RYGB will shed light on ways to mimic RYGB’s effects with less invasive alternative therapies. The central hypothesis will be tested in two specific aims: (1) to test the role of an unexpected luminal nutrient load to influence RL epigenetic and transcriptomic signatures for key genes associated with metabolically-significant RL remodeling; and (2) to test the dependency of RL epigenetic signatures and metabolic substrate utilization upon in vivo factors using intestinal epithelial organoids (IEOs). In aim 1, gene expression (RNA-seq) and chromatin remodeling (ATAC-seq) will be studied in RL versus bypassed intestinal limb (biliopancreatic limb) or versus sleeve gastrectomy, and these methods will also be employed to test the plasticity of RL remodeling during caloric restriction and refeeding. In aim 2, IEOs will be used to ask whether epigenetic (ATAC-seq) and metabolic reprogramming (RNA-seq; Seahorse XF Analysis) change in the absence of in vivo factors. The candidate for this career development award, Dr. Margaret Stefater, is a pediatric endocrinologist with an MD/PhD and expertise in the integrated physiology of energy balance, especially after bariatric surgery. In order to achieve scientific independence for the candidate, a comprehensive career development plan has been developed to gain additional experience in the areas of (1) epigenetics and gene regulatory networks, (2) bioinformatics, and (3) use of intestinal organoids as a model of intestinal biology. This will be accomplished through coursework and seminars, under the mentorship of experts in the fields of bariatric surgery (Nicholas Stylopoulos) and intestinal biology (David Breault). The proposed research in this application is innovative, in the applicant’s opinion, because it represents a substantial departure from the status quo by using state-of-the-art sequencing and bioinformatics techniques to address how RYGB’s core surgical elements (e.g., biliary exclusion, accelerated nutrient delivery) influence epigenetic regulation of gene expression. Ultimately, this project will shed light on mechanisms linking luminal factors to known intestinal remodeling after RYGB, thus highlighting potential novel drug targets for the development of innovative T2D therapies, and paving the way for the applicant’s first R01 submission.


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 = $0 )
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	11/14/2024	SUPPLEMENT FOR EXPANSION	$0
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $251,910 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/10/2023	NON-COMPETING CONTINUATION	$167,940
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	8/25/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/24/2023	SUPPLEMENT FOR EXPANSION	$83,970
														Subtotal = $251,910

Issue Date FY: 2022 ( Subtotal = $167,940 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/25/2022	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2021 ( Subtotal = $167,940 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/16/2021	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2020 ( Subtotal = $169,440 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/25/2020	NEW	$169,440
														Subtotal = $169,440

Grand Total All Awards = $757,230

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Role of intestinal luminal and epigenetic factors to mediate intestinal metabolic remodeling after gastric bypass surgery

Award Number: K08DK125878

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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