Wednesday, December 31, 2025 12/31/2025

Complement-mediated injury of the kidney: New mechanisms and novel therapies

Award Number: R01DK076690
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: 07/01/2008
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Complement-mediated injury of the kidney: New mechanisms and novel therapies - The alternative pathway of complement contributes to a wide range of glomerular diseases. Factor H is the main regulator of this innate immune cascade. Although some patients with kidney disease have underlying defects in factor H, complete deficiency of the protein is quite rare. It is not clear why kidney is so frequently the target of alternative pathway-mediated injury. One possible explanation is that endogenous proteins can function as factor H antagonists, effectively creating microenvironments locally deficient in the regulator. The factor H related proteins (FHRs), for example, antagonize binding of factor H to tissue surfaces, including the glomerular basement membrane (GBM). We have also discovered that another class of proteins - the annexins - act as factor H antagonists on kidney surfaces. Although the FHRs and annexins probably block factor H from binding other tissues in the body, the high concentration of alternative pathway proteins within the glomerular capillaries causes preferential activation at this location. Based on these findings, the primary hypothesis of this grant is that is that the GBM is uniquely susceptible to alternative pathway activation because the dysregulatory proteins (FHRs and annexins) effectively block factor H from binding this surface, yet it is simultaneously exposed to high concentrations of activating proteins. Alternative pathway activation within the glomerulus generates C3a and C5a, which ligate receptors on resident myeloid cells and create an inflammatory milieux within the kidney. Complement fragments generated in the kidney also stimulate T cells and B cells systemically. To test this hypothesis, the following specific aims will be pursued. Aim 1) Characterize the effects of dysregulatory proteins in the kidney. We will use in vitro and in vivo models to explore the molecular mechanisms that cause alternative pathway activation in the kidney. Aim 2. Examine the downstream effects of AP activation in the kidney. In this aim we will explore the downstream effects of glomerular complement activation on cells throughout the kidney. We will also examine whether complement activation in the glomeruli affects the adaptive immune response systemically. This could represent a mechanism by which inflammation in the kidney increases production of autoantibodies, creating a positive feed-back loop. Aim 3. Test novel strategies for blocking complement activation in the kidney. In this aim we will test the ability of novel engineered proteins to reverse alternative pathway dysregulation in the kidney. The project is expected to provide an overarching explanation for why the kidney - among all the organs - is so uniquely susceptible to alternative pathway-mediated injury. These studies will also test strategies for specifically blocking kidney inflammation. By targeting the underlying molecular triggers of complement activation in the kidney, drugs can be designed to inhibit these pathologic processes without blocking complement-mediated immunity systemically. This approach is expected to be both more effective and safer than currently available treatments.


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 = $468,016 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	12/18/2025	NON-COMPETING CONTINUATION	$468,016
														Subtotal = $468,016

Issue Date FY: 2025 ( Subtotal = $421,214 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	1/1/2025	NON-COMPETING CONTINUATION	$421,214
														Subtotal = $421,214

Issue Date FY: 2024 ( Subtotal = $449,294 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	5/15/2024	NON-COMPETING CONTINUATION	$28,080
2024	2024	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	12/18/2023	NON-COMPETING CONTINUATION	$421,214
														Subtotal = $449,294

Issue Date FY: 2023 ( Subtotal = $466,938 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	2/21/2023	COMPETING CONTINUATION	$468,016
2023	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	11/2/2022	NON-COMPETING CONTINUATION	-$1,078
														Subtotal = $466,938

Issue Date FY: 2021 ( Subtotal = $348,305 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	5/7/2021	NON-COMPETING CONTINUATION	$348,305
														Subtotal = $348,305

Issue Date FY: 2020 ( Subtotal = $499,148 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Trans-NIH Research Support	001	13	9/2/2020	SUPPLEMENT FOR EXPANSION	$150,835
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	5/18/2020	NON-COMPETING CONTINUATION	$348,313
														Subtotal = $499,148

Issue Date FY: 2019 ( Subtotal = $348,322 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	12	5/20/2019	NON-COMPETING CONTINUATION	$348,322
2019	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	11/15/2018	COMPETING CONTINUATION	$1,078
2019	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	11/15/2018	NON-COMPETING CONTINUATION	-$1,078
														Subtotal = $348,322

Issue Date FY: 2018 ( Subtotal = $360,817 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	11	7/19/2018	COMPETING CONTINUATION	$360,816
2018	2016	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	12/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$1,104
2018	2015	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/11/2017	NON-COMPETING CONTINUATION	-$1,103
														Subtotal = $360,817

Issue Date FY: 2017 ( Subtotal = $338,213 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	7/6/2017	NON-COMPETING CONTINUATION	$338,213
2017	2015	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	10/25/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $338,213

Issue Date FY: 2016 ( Subtotal = $338,213 )
2016	2016	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/14/2016	EXTENSION WITH OR WITHOUT FUNDS	$338,213
														Subtotal = $338,213

Issue Date FY: 2015 ( Subtotal = $338,213 )
2015	2015	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/30/2015	NON-COMPETING CONTINUATION	$338,213
														Subtotal = $338,213

Issue Date FY: 2014 ( Subtotal = $337,125 )
2014	2014	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/2/2014	NON-COMPETING CONTINUATION	$337,125
														Subtotal = $337,125

Issue Date FY: 2013 ( Subtotal = $336,038 )
2013	2013	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	9/18/2013	COMPETING CONTINUATION	$336,038
2013	2012	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/13/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,038

Issue Date FY: 2012 ( Subtotal = $305,409 )
2012	2012	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/30/2012	NON-COMPETING CONTINUATION	$305,409
														Subtotal = $305,409

Issue Date FY: 2011 ( Subtotal = $305,409 )
2011	2011	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/20/2011	NON-COMPETING CONTINUATION	$305,409
														Subtotal = $305,409

Issue Date FY: 2010 ( Subtotal = $310,789 )
2010	2010	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	9/2/2010	NON-COMPETING CONTINUATION	$2,295
2010	2010	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/30/2010	NON-COMPETING CONTINUATION	$308,494
														Subtotal = $310,789

Issue Date FY: 2009 ( Subtotal = $312,545 )
2009	2009	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/12/2009	NON-COMPETING CONTINUATION	$312,545
														Subtotal = $312,545

Issue Date FY: 2008 ( Subtotal = $313,480 )
2008	2008	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/3/2008	NEW	$313,480
														Subtotal = $313,480

Grand Total All Awards = $6,597,488

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Complement-mediated injury of the kidney: New mechanisms and novel therapies

Award Number: R01DK076690

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: 07/01/2008

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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