Tuesday, July 1, 2025 7/1/2025

Autophagy and LC3-associated phagocytosis in intestinal epithelial cells

Award Number: R01DK132074
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Autophagy and LC3-associated phagocytosis in intestinal epithelial cells - Abstract The intestinal epithelium is vital to maintain the barrier between the body and the outside world, and membrane trafficking is essential for both the development and maintenance of this barrier. Abnormal membrane trafficking can result compromised barrier leading to intestinal disease, including inflammatory bowel disease. Autophagy is a specialized membrane trafficking process that allows cells to respond to changes in metabolism. In addition, autophagy is important for maintenance of the epithelial barrier and the innate immune response, mediating the isolation and degradation of intracellular pathogens. Furthermore, LC3-associated phagocytosis (LAP) is important for uptake and degradation of pathogens, and dysfunction of this pathway is associated with hyperinflammation. Importantly, variants of proteins in the autophagic and LAP pathways have been linked to increased susceptibility to Inflammatory Bowel Disease (IBD), and particularly Crohn’s disease, although the molecular mechanisms that underlie this connection remain incompletely understood. MAMDC4 is an integral membrane protein that localizes to endosomes of the intestinal epithelium. Deletion of MAMDC4 compromises intestinal enterocyte morphology, and RNAseq studies have indicated that MAMDC4 is down- regulated in IBD. In previous work, we found that MAMDC4 interacts with the small GTPase Rab14. In professional phagocytes, Rab14 is recruited to phagosomes and prevents phagosome-lysosome fusion but its role in the intestinal epithelium is unknown. In our preliminary data, we show that Rab 14 is present on autophagosomes and both Rab14 and MAMDC4 are present on membranes containing invading bacteria. Furthermore, deletion of MAMDC4 results in accumulation of autophagy and lysosomal markers on tubular membranes. These results suggest that MAMDC4 and Rab14 act in a molecular network to maintain mucosal immunity through control of autophagy or LAP. In this proposal we will use intestinal epithelial cells in culture, organoid culture, and patient-derived organoids to define the role of autophagy and/or LAP in intestinal homeostasis.


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 = $450,877 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/19/2025	NON-COMPETING CONTINUATION	$450,877
														Subtotal = $450,877

Issue Date FY: 2024 ( Subtotal = $432,842 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/16/2024	NON-COMPETING CONTINUATION	$432,842
														Subtotal = $432,842

Issue Date FY: 2023 ( Subtotal = $450,877 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/23/2023	NON-COMPETING CONTINUATION	$450,877
														Subtotal = $450,877

Issue Date FY: 2022 ( Subtotal = $450,877 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/26/2022	NEW	$450,877
														Subtotal = $450,877

Grand Total All Awards = $1,785,473

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Autophagy and LC3-associated phagocytosis in intestinal epithelial cells

Award Number: R01DK132074

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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