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Studies on the Structure of Basement Membranes

Award Number: R01DK018381
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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Hundreds of variants in the COL4A3, COL4A4 and COL4A5 genes cause a broad range of glomerulopathies affecting the function of the glomerular basement membrane (GBM). These genes encode the assembly of collagen IV a345 scaffolds, the major constituent of the GBM, the autoantigen in Goodpasture’s (GP) autoimmune disease, and the protein mutated in Alport syndrome and other genetic glomerulopathies. GP disease has and continues to serve as the vanguard for unlocking mysteries of the molecular structure of the a345 scaffold and pathogenic mechanisms underlying both acquired and genetic glomerulopathies. Our overarching hypothesis is: Collagen IV a345 scaffold tethers macromolecules forming supramolecular complexes and perturbation of scaffold causes glomerulopathies. Four specific aims address key unanswered questions that are defined based on our previous and recent discoveries. Aim 1: a345NC1 Hexamer. To determine the atomic structure of the a345NC1 hexamer and mechanism of GP epitopes formation. The structure of the ¿345NC1 hexamer, GP autoantigen, is unknown. We hypothesize that upon perturbation of quaternary structure of the non-immunogenic ¿345NC1 hexamer, EA and EB regions undergo conformational changes forming pathogenic GP neoepitopes. Aim 2: a3 Zurich Mutation. To determine the impact of a3 Zurich mutation on GP epitopes formation. We found a mutation in a3NC1 domain associated with the first case of familial GP disease, providing genetic evidence for a triggering mechanism. We hypothesize that the mutation causes structural perturbation of the EA and EB regions of a3NC1, which can contribute to GP epitopes presentation. Aim 3. Chloride ring. To determine role of chloride in assembly of the collagen IV a345 scaffold and formation of GP epitopes. Whereas structure, assembly and functions of the a121 scaffold has been successfully studied for over 40 years, our knowledge about the a345 scaffold remains obscure. We demonstrated that chloride concentration is a critical factor in GP antibody binding. We hypothesize that assembly of the ¿345NC1 hexamer, its stability and GP-reactivity is dependent on chloride ions. Aim 4: a121 Supramolecular complexes. To characterize the supramolecular complexes of a121 collagen IV within a basement membrane. We discovered a garland architecture of the a121 scaffold coated with proteoglycans. This suprastructure is a potential core feature of basement membrane. We hypothesize that collagen IV a121 scaffold tethers macromolecules forming distinct supramolecular complexes which enable basement membrane assembly. The achievement of the aims will yield new insights to the etiology of GP disease and the structure and assembly of collagen IV scaffolds, leading to a framework for development of novel therapeutic strategies for GBM diseases.


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: 2023 ( Subtotal = $746,708 )
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	52	4/18/2023	NON-COMPETING CONTINUATION	$746,708
														Subtotal = $746,708

Issue Date FY: 2022 ( Subtotal = $747,082 )
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	51	4/29/2022	NON-COMPETING CONTINUATION	$747,082
														Subtotal = $747,082

Issue Date FY: 2021 ( Subtotal = $747,830 )
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	50	3/30/2021	NON-COMPETING CONTINUATION	$747,830
														Subtotal = $747,830

Issue Date FY: 2020 ( Subtotal = $812,466 )
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	006	49	8/25/2020	COMPETING CONTINUATION	$0
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	002	49	3/5/2020	COMPETING CONTINUATION	$746,708
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	007	49	9/3/2020	SUPPLEMENT FOR EXPANSION	$65,758
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	004	49	8/4/2020	COMPETING CONTINUATION	$420,180
2020	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	48	2/21/2020	NON-COMPETING CONTINUATION	$0
2020	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	48	8/4/2020	SUPPLEMENT FOR EXPANSION	-$46,847
2020	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	48	2/21/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	48	8/4/2020	NON-COMPETING CONTINUATION	-$373,333
														Subtotal = $812,466

Issue Date FY: 2019 ( Subtotal = $741,902 )
2019	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	48	8/8/2019	NON-COMPETING CONTINUATION	$695,055
2019	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	48	8/28/2019	SUPPLEMENT FOR EXPANSION	$46,847
														Subtotal = $741,902

Issue Date FY: 2018 ( Subtotal = $878,858 )
2018	2018	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	47	6/7/2018	NON-COMPETING CONTINUATION	$878,858
														Subtotal = $878,858

Issue Date FY: 2017 ( Subtotal = $878,858 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	46	8/10/2017	NON-COMPETING CONTINUATION	$730,605
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	46	9/11/2017	SUPPLEMENT FOR EXPANSION	$148,253
														Subtotal = $878,858

Issue Date FY: 2016 ( Subtotal = $709,744 )
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	005	45	9/16/2016	NON-COMPETING CONTINUATION	-$709,275
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	006	45	9/17/2016	NON-COMPETING CONTINUATION	$709,275
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	003	45	9/12/2016	NON-COMPETING CONTINUATION	$704,786
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	004	45	9/15/2016	NON-COMPETING CONTINUATION	$4,489
2016	2015	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	44	7/12/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$74,069
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	002	43	7/13/2016	COMPETING CONTINUATION	-$26,721
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	000	43	5/24/2016	COMPETING CONTINUATION	-$46,879
														Subtotal = $709,744

Issue Date FY: 2015 ( Subtotal = $704,786 )
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	43	9/15/2015	COMPETING CONTINUATION	$704,786
														Subtotal = $704,786

Issue Date FY: 2014 ( Subtotal = $567,177 )
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	42	8/7/2014	NON-COMPETING CONTINUATION	$567,177
														Subtotal = $567,177

Issue Date FY: 2013 ( Subtotal = $563,742 )
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	41	8/8/2013	NON-COMPETING CONTINUATION	$563,742
														Subtotal = $563,742

Issue Date FY: 2012 ( Subtotal = $598,867 )
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	40	8/16/2012	NON-COMPETING CONTINUATION	$598,867
														Subtotal = $598,867

Issue Date FY: 2011 ( Subtotal = $731,157 )
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	39	8/26/2011	NON-COMPETING CONTINUATION	$666,390
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	38	3/4/2011	SUPPLEMENT FOR EXPANSION	$64,767
														Subtotal = $731,157

Issue Date FY: 2010 ( Subtotal = $737,042 )
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	38	9/7/2010	COMPETING CONTINUATION	$737,042
														Subtotal = $737,042

Issue Date FY: 2000 ( Subtotal = $375,000 )
2000	2000	UNIVERSITY OF KANSAS, MEDICAL CENTER	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	8/14/2000	COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 1999 ( Subtotal = $360,759 )
1999	1999	UNIVERSITY OF KANSAS, MEDICAL CENTER	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	8/19/1999	NON-COMPETING CONTINUATION	$360,759
														Subtotal = $360,759

Issue Date FY: 1998 ( Subtotal = $349,617 )
1998	1998	UNIVERSITY OF KANSAS, MEDICAL CENTER	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	8/31/1998	NON-COMPETING CONTINUATION	$349,617
														Subtotal = $349,617

Grand Total All Awards = $11,251,595

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Studies on the Structure of Basement Membranes

Award Number: R01DK018381

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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