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Induction and Evolution of Metaplasia in the Stomach

Award Number: R01DK101332
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: 05/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Induction and Evolution of Metaplasia in the Stomach - In the stomach, metaplasia arises in the setting of parietal cell loss or oxyntic atrophy. Two types of metaplasia occur in the human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the corpus of the stomach). Investigations over the past decade have led to the recognition that SPEM lineages are substantially derived from transdifferentiation of protein secreting chief cells into mucus-secreting SPEM lineages. In addition, increasing evidence suggests that SPEM represents a physiological local repair lineage that is meant to promote local restitution and then be replaced by normal lineages. Importantly, the induction of SPEM from chief cells is orchestrated by release of IL-13 from ILC2 intrinsic mucosal immune cells. Elimination of ILC2s blocks the development of SPEM following acute parietal cell loss. In the setting of chronic injury and inflammation, in addition to alterations in the inflammatory cells within the metaplastic milieu, there is a resculpting of the stromal fibroblasts that likely supports the altered metaplastic stem cell niche. We have identified the relocalization of telocyte fibroblast populations to the bases of metaplastic glands following acute oxyntic atrophy in mice. In addition, we have identified four distinct populations of fibroblast in the normal and diseased human stomach. Together these findings suggest that intrinsic mucosal inflammatory cells and fibroblasts within the parenchyma of the metaplastic niche may promote the maintenance of metaplastic cell lineages as well as their progression to more proliferative and intestinalized pre-neoplastic lineages. We have hypothesized that intrinsic immune cell populations and altered fibroblasts promote a remodeled tissue milieu that promotes progression towards neoplasia in the stomach. To evaluate this hypothesis, we will examine two specific aims: First, we will determine how expansion of ILC2s promotes metaplasia and its progression. Specifically, we will examine the effects of IL-13 and or ILC2- co-culture with metaplastic gastroids to promote progression of metaplasia. Additionally, we will define the transcriptional regulation initiated by IL-13 mediated activation of STAT6 that accounts for induction of metaplasia progression. Second, we will define specific fibroblast populations that promote the development of an altered pre-neoplastic milieu in the gastric mucosa. We will assess the dynamics of telocyte populations in the establishment of the metaplastic milieu in mice and evaluate their ability to promote metaplastic progression in vitro in co-culture. We will further isolate fibroblast sub-populations from regions of normal, metaplastic, and cancerous human gastric mucosa to define alterations in fibroblast sub-populations that may promote a pre-neoplastic niche in the metaplastic mucosa. These studies will establish in greater detail how immune cell and fibroblast populations contribute to the development of a pre-cancerous milieu in the stomach and will allow the identification of strategies that can arrest or reverse progression from metaplasia to cancer.


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 = $535,314 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	5/26/2025	NON-COMPETING CONTINUATION	$535,314
														Subtotal = $535,314

Issue Date FY: 2024 ( Subtotal = $513,901 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	5/31/2024	NON-COMPETING CONTINUATION	$513,901
2024	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	5/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $513,901

Issue Date FY: 2023 ( Subtotal = $535,314 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	5/31/2023	NON-COMPETING CONTINUATION	$535,314
														Subtotal = $535,314

Issue Date FY: 2022 ( Subtotal = $535,314 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	7/18/2022	COMPETING CONTINUATION	$535,314
2022	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/8/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $535,314

Issue Date FY: 2021 ( Subtotal = $469,692 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/9/2021	NON-COMPETING CONTINUATION	$469,692
														Subtotal = $469,692

Issue Date FY: 2020 ( Subtotal = $472,614 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/17/2020	NON-COMPETING CONTINUATION	$472,614
														Subtotal = $472,614

Issue Date FY: 2019 ( Subtotal = $475,482 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	4/16/2019	NON-COMPETING CONTINUATION	$475,482
2019	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	12/6/2018	COMPETING CONTINUATION	$46,941
2019	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/6/2018	NON-COMPETING CONTINUATION	-$46,941
														Subtotal = $475,482

Issue Date FY: 2018 ( Subtotal = $506,766 )
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/9/2018	COMPETING CONTINUATION	$404,831
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	9/14/2018	COMPETING CONTINUATION	$101,935
2018	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/4/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $506,766

Issue Date FY: 2017 ( Subtotal = $343,347 )
2017	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/17/2017	NON-COMPETING CONTINUATION	$309,012
2017	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	6/15/2017	NON-COMPETING CONTINUATION	$34,335
2017	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	6/12/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,475
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/12/2017	NON-COMPETING CONTINUATION	-$4,475
														Subtotal = $343,347

Issue Date FY: 2016 ( Subtotal = $343,347 )
2016	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,347
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/29/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,347

Issue Date FY: 2015 ( Subtotal = $341,177 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/1/2015	NON-COMPETING CONTINUATION	$341,177
														Subtotal = $341,177

Issue Date FY: 2014 ( Subtotal = $340,816 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/1/2014	NEW	$340,816
														Subtotal = $340,816

Grand Total All Awards = $5,413,084

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Induction and Evolution of Metaplasia in the Stomach

Award Number: R01DK101332

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: 05/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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