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Development and vascularity of intestinal mesenchyme

Award Number: R01DK121540
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: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Development and vascularity of intestinal mesenchyme - Project Summary Adult digestive epithelia depend on adjacent mesenchyme to sustain intestinal stem cells (ISCs) at the crypt base and drive cell maturation at the villus base. Precisely layered cells that provide redundant and partially overlapping “trophic” factors execute these essential polarized functions. Our lab’s contributions to this emerging understanding include deep characterization of small intestine (SI) and colonic mesenchyme, discovery of potent “trophocytes,” a cellular explanation for the crypt BMP signaling gradient, identification of the authentic source of canonical Wnt ligands, and discovery of niche self-organization. Importantly, work from several groups converges on nearly identical consensus cell populations in mouse and human intestines. Strategically localized fractions of the most abundant cells (which express low PDGFRA), including distinct CD81+ trophocytes, represent notable functional niche elements. In the developing gut mesoderm, PDGFRAlo cells seem to give rise to key structural elements, such as different smooth muscle (SM) compartments and unique intestinal capillaries, before the remaining PDGFRAlo cells generate the ISC niche. Against the backdrop of a complete census of adult mesenchymal cells, these findings pave the way to understand their embryonic origins in modern mechanistic terms. This simple but crucial tissue thus offers opportunities to address a broad, fundamental question in developmental biology: How does an embryonic anlage with limited external cell input achieve and retain its adult form? Because injured intestines must reconstitute the mesenchymal compartment, the answers have important implications for understanding and treating ulcerative and other forms of intestinal damage. Prior investigation of signaling in intestinal development elegantly implicates Hedgehog (Hh, from endoderm) and BMP (from mesoderm) in specifying at least SM and endothelial cells (EC), and possibly other compartments, but how these signals elicit distinct cell fates in ostensibly similar progenitors remains unclear. Discrete cell identities reflect opening and closing of thousands of different cis-regulatory elements (CREs); to deconstruct steps that lie between a mesodermal anlage and the functional tissue into which it develops, we propose to study the chromatin basis of SM (Aim 1) and EC (Aim 2) differentiation. We will map mesenchymal ontogeny rigorously with respect to signature CREs for each resident cell type (Aims 1A and 1B), then investigate in primary fetal cell cultures how Hh activity and BMP inhibition together induce the CRE complement necessary for naïve precursors to undergo SM differentiation (Aim 1C). We then ask how the same signals (albeit likely in different forms or concentrations) induce ECs in similar progenitors (Aim 2A). Finally, we propose studies for mechanistic insight into processes designed for intestinal capillary growth to match, but not exceed, resting tissue demands (Aim 2B). Together, this basic science effort aims for fundamental knowledge about a tissue that is critical for intestinal function in resting and injured states.


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 = $448,104 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/24/2026	NON-COMPETING CONTINUATION	$448,104
														Subtotal = $448,104

Issue Date FY: 2025 ( Subtotal = $448,104 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	5/8/2025	NON-COMPETING CONTINUATION	$448,104
														Subtotal = $448,104

Issue Date FY: 2024 ( Subtotal = $430,180 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/10/2024	NON-COMPETING CONTINUATION	$430,180
2024	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/5/2024	COMPETING CONTINUATION	$18,033
2024	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/5/2024	NON-COMPETING CONTINUATION	-$18,033
														Subtotal = $430,180

Issue Date FY: 2023 ( Subtotal = $448,104 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/14/2023	COMPETING CONTINUATION	$448,104
2023	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $448,104

Issue Date FY: 2022 ( Subtotal = $378,317 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/28/2022	NON-COMPETING CONTINUATION	$378,317
														Subtotal = $378,317

Issue Date FY: 2021 ( Subtotal = $378,317 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/1/2021	NON-COMPETING CONTINUATION	$378,317
														Subtotal = $378,317

Issue Date FY: 2020 ( Subtotal = $378,317 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/16/2020	NON-COMPETING CONTINUATION	$378,317
														Subtotal = $378,317

Issue Date FY: 2019 ( Subtotal = $373,122 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/6/2019	NEW	$2,848
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/23/2019	NEW	$370,274
														Subtotal = $373,122

Grand Total All Awards = $3,282,565

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Development and vascularity of intestinal mesenchyme

Award Number: R01DK121540

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: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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