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The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration

Award Number: R01DK095004
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The receptor tyrosine kinases ErbB4 and ErbB3 can protect intestinal enterocytes from apoptosis, but their potential roles in inducing stem cell regeneration after an insult—arguably of equal importance in the face of challenge—are not known. Here, we aim to define the function of ErbB3 and ErbB4 in post-injury recovery of intestinal stem cells, and thus in regeneration of the epithelium. ErbB4 expression is high in regenerating enteroids, and the ErbB4 ligand NRG4 promotes crypt plating efficiency. ErbB4-null enteroid cultures have a compromised intestinal stem cell niche with loss of the rapidly-cycling stem cell marker Lgr5 and reduced Paneth cell numbers. Similar to ErbB4, ErbB3 promotes enterocyte survival, but unlike ErbB4 it suppresses secretory cell differentiation; for example, ErbB3-null enteroids have an expanded Paneth cell census. Thus, the two neuregulin receptors seem to play complementary but distinct roles in regulating renewal and development in the crypt. Preliminary data suggest that both of these receptors are induced during recovery from injury models in vitro and in vivo, and loss of either perturbs recovery. We will build on our published and preliminary data to test the hypothesis that signaling through ErbB4 and ErbB3 promotes balanced regeneration of the intestinal epithelium after injury. We will (1) define the impact of ErbB4 or ErbB3 loss or activation on intestinal epithelial regeneration after injury, (2) determine the molecular mechanisms linking ErbB4 and ErbB3 to intestinal stem cell regeneration, especially connections to the fundamental regulators of stem cell self-renewal, Wnt and Notch. These studies will advance basic understanding of how intestinal stem cells and the stem cell niche are repaired, as well as identify novel regulatory mechanisms that could be future therapeutic targets to drive intestinal regeneration after 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: 2022 ( Subtotal = $421,321 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/23/2022	NON-COMPETING CONTINUATION	$421,321
														Subtotal = $421,321

Issue Date FY: 2021 ( Subtotal = $421,741 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	5/12/2021	NON-COMPETING CONTINUATION	$421,741
														Subtotal = $421,741

Issue Date FY: 2020 ( Subtotal = $422,148 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	5/12/2020	NON-COMPETING CONTINUATION	$422,148
														Subtotal = $422,148

Issue Date FY: 2019 ( Subtotal = $457,153 )
2019	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/27/2019	COMPETING CONTINUATION	$457,153
2019	2017	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $457,153

Issue Date FY: 2017 ( Subtotal = $352,350 )
2017	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	6/16/2017	NON-COMPETING CONTINUATION	$35,235
2017	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	5/8/2017	NON-COMPETING CONTINUATION	$317,115
2017	2016	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	11/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$166,321
2017	2015	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/21/2016	NON-COMPETING CONTINUATION	-$166,321
														Subtotal = $352,350

Issue Date FY: 2016 ( Subtotal = $352,350 )
2016	2016	CHILDRENS HOSPITAL OF LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/17/2016	EXTENSION WITH OR WITHOUT FUNDS	$352,350
														Subtotal = $352,350

Issue Date FY: 2015 ( Subtotal = $352,350 )
2015	2015	CHILDRENS HOSPITAL OF LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/5/2015	NON-COMPETING CONTINUATION	$352,350
														Subtotal = $352,350

Issue Date FY: 2014 ( Subtotal = $352,350 )
2014	2014	CHILDRENS HOSPITAL OF LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/21/2014	NON-COMPETING CONTINUATION	$352,350
														Subtotal = $352,350

Issue Date FY: 2013 ( Subtotal = $352,350 )
2013	2013	CHILDRENS HOSPITAL OF LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/4/2013	NEW	$352,350
														Subtotal = $352,350

Grand Total All Awards = $3,484,113

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The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration

Award Number: R01DK095004

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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