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Autophagy, injury, and plasticity in the intestinal regenerative process

Award Number: R01DK142682
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: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Autophagy, injury, and plasticity in the intestinal regenerative process - PROJECT SUMMARY The intestinal lining is supported via maintenance of a layer of intestinal epithelial cells, and in particular, intestinal stem cells (ISCs). ISCs are very sensitive to cell death in response to various injuries, including radiation, chemotherapy, or inflammation. In the face of ISC depletion, the epithelial layer can still efficiently regenerate due to the contribution of other cells that can re-acquire ISC activity when needed, termed “facultative” intestinal stem cells (f-ISCs). F-ISCs must possess two fundamental attributes: 1) injury resistance, and 2) the ability to re-acquire ISC activity. These attributes together ensure replenishment of the epithelial lining in response to tissue damage. Despite the critical importance of f-ISC activity in the regenerative response, little is known about its molecular basis. Emerging evidence implicates autophagy as a key player in this process. Genetic inactivation of autophagy leads to reduced regeneration after epithelial injury, and polymorphisms in autophagy genes are associated with susceptibility to Crohn's disease. Conversely, calorie restriction or fasting, which can induce autophagy, is associated with enhanced intestinal regeneration. Our recent publication showed that intestinal cells with high autophagic vesicle content are relatively resistant to DNA damage compared to ISCs in vivo. We also find that high autophagic vesicle content in intestinal epithelial cells, particularly differentiated secretory cells, is associated with enhanced organoid formation- an in vitro proxy for ISCs. These data suggest that high autophagic vesicle content can prospectively identify secretory cells that are f-ISCs in vitro, however, whether certain lineages are better “poised” to be f-ISCs and the mechanistic contribution of autophagy to both injury resistance and regeneration are critical knowledge gaps. The current proposal will use in vivo models and organoids from both mice and humans to define how autophagy contributes to cells that survive injury and re-enter the cell cycle to drive regeneration. Aim 1 will define whether autophagy, and specifically mitophagy, underlies DNA damage resistance of f-ISCs. Key findings will be confirmed in enteroids and colonoids from de-identified healthy human subjects. Aim 2 will define the extent to which autophagy-mediated f-ISCs utilize a TGF-mediated fetal gene expression program to contribute to tissue regeneration. Key facets of Aim 2 will be evaluated directly in human organoid lines. Our study will provide a significant conceptual advance in understanding how non-ISCs with high autophagy can repurpose themselves as f-ISCs to contribute to epithelial barrier restoration. In addition, these studies are highly impactful because they will directly translate key findings in primary human cells. Resulting data will form a basis for enhancing f-ISCs for clinical benefit in patients with GI diseases.


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 = $824,562 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/21/2026	NON-COMPETING CONTINUATION	$824,562
														Subtotal = $824,562

Issue Date FY: 2025 ( Subtotal = $836,942 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/8/2025	NEW	$836,942
														Subtotal = $836,942

Grand Total All Awards = $1,661,504

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Autophagy, injury, and plasticity in the intestinal regenerative process

Award Number: R01DK142682

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: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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