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Mechanisms of EGFR Activation and Signaling in Kidney Disease

Award Number: R01DK051265
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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Mechanisms of EGFR Activation and Signaling in Kidney Disease - The Epidermal Growth Factor Receptor (EGFR) is a member of the family of ErbB receptors, which consist of an extracellular ligand-binding domain, a single membrane-spanning region, a homologic cytoplasmic protein tyrosine kinase domain and a C-terminal tail with multiple phosphorylation sites. EGFR can be activated by a family of ligands (including EGF, TGF-a, HB-EGF, amphiregulin, epiregulin and betacellulin) that bind and induce receptor autophosphorylation and activation of intracellular signaling pathways. Transactivation of the EGFR receptor occurs by activation of ADAM-mediated cleavage and release of active EGFR ligands, with ADAM17 (TACE) mediating release of HB-EGF, amphiregulin, TGF-a and epiregulin. We and others have reported EGFR to be a mediator of fibrosis in chronic progressive kidney disease, including diabetic nephropathy, RPGN, chronic allograft nephropathy and PKD. Either genetic or pharmacologic inhibition of EGFR activation can be an effective therapeutic intervention in experimental models of progressive kidney disease, but the mechanisms by which EGFR activation mediates development of progressive chronic kidney injury are still incompletely understood. EGFR and its ligands are expressed in a variety of cell types including cells of myeloid origin. We and others have defined an important role for myeloid derived cells in propagation of acute kidney injury and in the development of chronic renal damage, but the role of renal myeloid cell EGFR and its ligands in progressive kidney injury has not been previously studied. Our recent preliminary studies indicate that EGFR signaling is a mediator of inflammatory macrophage actions in the kidney. As indicated in Preliminary Results, activation of myeloid EGFR as well as expression of its ligand, amphiregulin (AREG), appear to play an important role in post-ischemic renal injury and in development of progressive renal fibrosis. In addition, recent studies demonstrate that iRhom2, an inactive member of the Rhomboid intramembrane proteinase family, mediates myeloid cell-specific activation of TACE and secretion of amphiregulin and HB-EGF, as well as TNF-a without affecting ligand release in other organs, raising the possibility that targeting iRhom2 could be a potentially efficacious approach to limit development or progression of CKD. We propose to investigate the role of the renal myeloid EGFR axis in development of chronic renal fibrosis in three specific aims: Aim I Determine the role of EGFR in macrophage activation in kidney disease Aim II Determine the role of amphiregulin in mediation of development of tubulointerstitial fibrosis with progressive kidney injury Aim III Determine the role of iRhom2 (Rhomboid 5 homolog 2 (RHBDF2)) activation in mediation of renal myeloid cell-mediated tubulointerstitial fibrosis


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: 2024 ( Subtotal = $574,553 )
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	000	28	12/5/2023	NON-COMPETING CONTINUATION	$538,642
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	28	5/2/2024	NON-COMPETING CONTINUATION	$35,911
														Subtotal = $574,553

Issue Date FY: 2023 ( Subtotal = $598,492 )
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	27	1/16/2023	NON-COMPETING CONTINUATION	$598,492
														Subtotal = $598,492

Issue Date FY: 2022 ( Subtotal = $598,492 )
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	26	3/29/2022	NON-COMPETING CONTINUATION	$59,850
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	000	26	12/21/2021	NON-COMPETING CONTINUATION	$538,642
														Subtotal = $598,492

Issue Date FY: 2021 ( Subtotal = $598,492 )
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	25	11/27/2020	COMPETING CONTINUATION	$588,113
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	002	25	7/31/2021	COMPETING CONTINUATION	$103,338
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	003	25	9/14/2021	COMPETING CONTINUATION	$10,379
2021	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	7/31/2021	NON-COMPETING CONTINUATION	-$103,338
														Subtotal = $598,492

Issue Date FY: 2019 ( Subtotal = $462,520 )
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	000	24	1/3/2019	NON-COMPETING CONTINUATION	$462,520
														Subtotal = $462,520

Issue Date FY: 2018 ( Subtotal = $462,520 )
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	000	23	12/14/2017	NON-COMPETING CONTINUATION	$416,268
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	23	4/25/2018	NON-COMPETING CONTINUATION	$46,252
														Subtotal = $462,520

Issue Date FY: 2017 ( Subtotal = $462,520 )
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	001	22	6/22/2017	NON-COMPETING CONTINUATION	$46,253
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	22	1/24/2017	NON-COMPETING CONTINUATION	$416,267
														Subtotal = $462,520

Issue Date FY: 2016 ( Subtotal = $462,520 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	8/1/2016	NON-COMPETING CONTINUATION	-$459,592
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	002	21	8/2/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$462,520
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	3/2/2016	NON-COMPETING CONTINUATION	$459,592
														Subtotal = $462,520

Issue Date FY: 2015 ( Subtotal = $459,592 )
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	002	19	3/1/2015	COMPETING CONTINUATION	$459,592
2015	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	1/27/2015	NON-COMPETING CONTINUATION	$0
2015	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	18	12/18/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,592

Issue Date FY: 2014 ( Subtotal = $320,463 )
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	18	3/7/2014	NON-COMPETING CONTINUATION	$320,463
														Subtotal = $320,463

Issue Date FY: 2013 ( Subtotal = $309,247 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	2/22/2013	NON-COMPETING CONTINUATION	$288,416
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	5/15/2013	NON-COMPETING CONTINUATION	$20,831
														Subtotal = $309,247

Issue Date FY: 2012 ( Subtotal = $320,463 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	5/2/2012	NON-COMPETING CONTINUATION	$320,463
														Subtotal = $320,463

Issue Date FY: 2011 ( Subtotal = $319,778 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	6/7/2011	NON-COMPETING CONTINUATION	$29,070
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/24/2011	NON-COMPETING CONTINUATION	$290,708
														Subtotal = $319,778

Issue Date FY: 2010 ( Subtotal = $387,500 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/12/2010	COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2009 ( Subtotal = $313,797 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	2/2/2009	NON-COMPETING CONTINUATION	$0
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	12/22/2008	NON-COMPETING CONTINUATION	$282,417
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	13	3/4/2009	NON-COMPETING CONTINUATION	$31,380
														Subtotal = $313,797

Issue Date FY: 2008 ( Subtotal = $313,797 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Kidney Diseases, Urology and Hematology Research	000	12	2/4/2008	NON-COMPETING CONTINUATION	$313,797
														Subtotal = $313,797

Issue Date FY: 2007 ( Subtotal = $319,680 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Kidney Diseases, Urology and Hematology Research	000	11	1/9/2007	NON-COMPETING CONTINUATION	$319,680
														Subtotal = $319,680

Issue Date FY: 2006 ( Subtotal = $327,616 ) (Continued on the next page)
Grand Total All Awards = $9,730,894

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Mechanisms of EGFR Activation and Signaling in Kidney Disease

Award Number: R01DK051265

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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