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Investigating the Intersection of Metabolism and NAD+-Consuming Enzymes in Intestinal Homeostasis and Disease.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating the Intersection of Metabolism and NAD+-Consuming Enzymes in Intestinal Homeostasis and Disease./
Author:	Tucker, Sarah Anne.
Description:	1 online resource (242 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29209118click for full text (PQDT)
ISBN:	9798819375600

Investigating the Intersection of Metabolism and NAD+-Consuming Enzymes in Intestinal Homeostasis and Disease.
Tucker, Sarah Anne.

Investigating the Intersection of Metabolism and NAD+-Consuming Enzymes in Intestinal Homeostasis and Disease. - 1 online resource (242 pages)

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

The intestinal epithelium displays remarkable resistance to damaging stress to maintain intestinal nutrient uptake and barrier functions. Dysregulation of pathways regulating intestinal homeostasis can lead to diseases such as inflammatory bowel disease (IBD) and colon cancer (CRC). Cellular metabolic state and NAD+ availability play key roles in coordinating how the intestinal niche responds to stress. Metabolic adaptation and tissue NAD+ balance are tightly linked, in part through activity of NAD+-consuming enzymes. Despite emerging roles for NAD+-consuming enzymes in intestinal function and disease, how NAD+ degradation pathways interface with metabolic activity to maintain homeostasis remains unclear. Thus, the goal of this dissertation was to develop a better understanding of how interplay between NAD+-degrading enzyme activities and metabolic rewiring contributes to intestinal homeostasis and disease. In this dissertation, I describe three studies that shed light on interaction between NAD+-consuming activities and metabolic reprogramming in the intestine. First, we discovered that the mitochondrial sirtuin SIRT4 regulates metabolism and stress response in the intestinal niche. We found that crypts from intestine-specific SIRT4 null (KO) mice were hyperproliferative following irradiation, and SIRT4 KO mice with mutant APC displayed increased tumorigenesis and dysregulated tumor metabolism. Studies in SIRT4 KO intestinal organoids revealed increased survival following irradiation stress, elevated glutamine uptake, and increased de novo nucleotide synthesis rates. Inhibition of de novo nucleotide synthesis in SIRT4 KO organoids was sufficient to reduce survival to WT levels post-irradiation. Second, we uncovered a link between dysregulated NAD+ metabolism and mitochondrial dysfunction in ulcerative colitis (UC). Metabolomic profiling of UC patient biopsies revealed a reduced NAD+/NAM ratio in inflamed colon tissue, and electron microscopy analysis of UC biopsies showed altered mitochondrial morphology. Finally, we developed an LC-MS platform to study O-acyl-ADP-ribose (OAcADPr) metabolites resulting from sirtuin-mediated NAD+ degradation. Our LC-MS approach detected endogenous OAcADPr and confirmed enzymatic regulation of OAcADPr levels in human CRC cells, opening the door for future studies of OAcADPr regulation in normal physiology and disease. In sum, these findings contribute to our understanding of interplay between metabolic reprogramming and NAD+ degrading activities in the intestinal niche, revealing potential pathways for therapeutic intervention in intestinal disease states.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798819375600Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

MetabolismIndex Terms--Genre/Form:

542853
Electronic books.

Investigating the Intersection of Metabolism and NAD+-Consuming Enzymes in Intestinal Homeostasis and Disease.
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520 $a The intestinal epithelium displays remarkable resistance to damaging stress to maintain intestinal nutrient uptake and barrier functions. Dysregulation of pathways regulating intestinal homeostasis can lead to diseases such as inflammatory bowel disease (IBD) and colon cancer (CRC). Cellular metabolic state and NAD+ availability play key roles in coordinating how the intestinal niche responds to stress. Metabolic adaptation and tissue NAD+ balance are tightly linked, in part through activity of NAD+-consuming enzymes. Despite emerging roles for NAD+-consuming enzymes in intestinal function and disease, how NAD+ degradation pathways interface with metabolic activity to maintain homeostasis remains unclear. Thus, the goal of this dissertation was to develop a better understanding of how interplay between NAD+-degrading enzyme activities and metabolic rewiring contributes to intestinal homeostasis and disease. In this dissertation, I describe three studies that shed light on interaction between NAD+-consuming activities and metabolic reprogramming in the intestine. First, we discovered that the mitochondrial sirtuin SIRT4 regulates metabolism and stress response in the intestinal niche. We found that crypts from intestine-specific SIRT4 null (KO) mice were hyperproliferative following irradiation, and SIRT4 KO mice with mutant APC displayed increased tumorigenesis and dysregulated tumor metabolism. Studies in SIRT4 KO intestinal organoids revealed increased survival following irradiation stress, elevated glutamine uptake, and increased de novo nucleotide synthesis rates. Inhibition of de novo nucleotide synthesis in SIRT4 KO organoids was sufficient to reduce survival to WT levels post-irradiation. Second, we uncovered a link between dysregulated NAD+ metabolism and mitochondrial dysfunction in ulcerative colitis (UC). Metabolomic profiling of UC patient biopsies revealed a reduced NAD+/NAM ratio in inflamed colon tissue, and electron microscopy analysis of UC biopsies showed altered mitochondrial morphology. Finally, we developed an LC-MS platform to study O-acyl-ADP-ribose (OAcADPr) metabolites resulting from sirtuin-mediated NAD+ degradation. Our LC-MS approach detected endogenous OAcADPr and confirmed enzymatic regulation of OAcADPr levels in human CRC cells, opening the door for future studies of OAcADPr regulation in normal physiology and disease. In sum, these findings contribute to our understanding of interplay between metabolic reprogramming and NAD+ degrading activities in the intestinal niche, revealing potential pathways for therapeutic intervention in intestinal disease states.
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