Tuesday, July 8, 2025 7/8/2025

A molecular and physical mechanism for growing and branching the intestinal villus

Award Number: R01DK126376
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: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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A molecular and physical mechanism for growing and branching the intestinal villus - ABSTRACT Villi are finger-like projection that line the lumen of the small intestine where they aid in nutrient uptake by increasing the intestinal absorptive surface area. Villus atrophy causes major digestive complications and nutrient malabsorption. Abnormalities in villi are found in many gastrointestinal maladies, such as inflammatory bowel and celiac diseases, and are also side effects of radiation, chemotherapy, and infection. Degenerated villi can sometimes fully reform, but persistent villus atrophy causes severe complications and patient suffering. Thus, understanding the molecular and mechanical mechanisms underlying villus formation and repair are essential to develop new therapies and for growing and regenerating intestinal tissue for human patients. Villi emerge during development from an initially flat intestinal surface. We recently demonstrated that the forces necessary and sufficient to pattern and fold the epithelium during the initiation of villus morphogenesis derive from a population of Pdgfrahigh cells that differentiate at the interface of the epithelium and mesenchyme. These cells form a motile monolayer that breaks up into compact aggregates that fold the overlying epithelium in a Myosin-II, Hedgehog, MMP and integrin-dependent manner. We named this process “active mesenchymal dewetting.” Following this critical symmetry-breaking event, however, villi must increase their length by at least four-fold. This process coincides with the differentiation of the overlying epithelium into Wnt-responsive proliferative domains in between villi, and non-proliferative domains overlying villi. Finally, villus initiation and extension repeats itself at least four more time in a manner highly reminiscent of branching morphogenesis. Guided by our findings in revealing the mechanism of villus initiation, we propose to test three hypotheses related to the molecular and mechanical processes driving villus extension, villus branching, and epithelial zonation. First, we hypothesize that forces driving villus extension derive from a transition of proliferative, dynamic and narrow epithelial cells, to a non-proliferative, static, and wide morphology as they move into villus domains. Second, we hypothesize that epithelial zonation derives from Pdgfrahigh clusters physically pushing the overlying epithelium away from a critical source of Rspo2 and 3 in the deep mesenchyme. Third, we hypothesize that repeated rounds of villus “branching” occur when the intervillus proliferative epithelium “pushes” into the mesenchyme, causing it to thin, and exposing a population of Pdgfralow cells in the deep mesenchyme to the surface where they come in contact with epithelial hedgehog and differentiate. We will test these hypotheses using an innovative combination of live imaging, mouse genetics, computational modeling, and mechanical perturbations. This project has major implications for our understanding of the developmental of the gut and for tissue engineering because it will provide a new mechanistic blueprint for building villi incorporating both signals and forces. These findings will also lay the groundwork for future studies of regeneration: the adult sub-epithelial mesenchyme retains expression of many of these cell types and many are activated following injury.


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 = $678,386 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/27/2024	COMPETING CONTINUATION	$678,386
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	5/23/2025	COMPETING CONTINUATION	$228,133
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	5/23/2025	NON-COMPETING CONTINUATION	-$228,133
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $678,386

Issue Date FY: 2024 ( Subtotal = $546,769 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/20/2024	NON-COMPETING CONTINUATION	$546,769
														Subtotal = $546,769

Issue Date FY: 2023 ( Subtotal = $569,551 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/12/2023	NON-COMPETING CONTINUATION	$569,551
														Subtotal = $569,551

Issue Date FY: 2022 ( Subtotal = $569,551 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/16/2022	NON-COMPETING CONTINUATION	$569,551
														Subtotal = $569,551

Issue Date FY: 2021 ( Subtotal = $570,475 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/25/2021	NON-COMPETING CONTINUATION	$570,475
														Subtotal = $570,475

Issue Date FY: 2020 ( Subtotal = $584,002 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/14/2020	NEW	$584,002
														Subtotal = $584,002

Grand Total All Awards = $3,518,734

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A molecular and physical mechanism for growing and branching the intestinal villus

Award Number: R01DK126376

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: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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