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Molecular Pathobiology of Alport Syndrome

Award Number: R01DK131101
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: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Molecular Pathobiology of Alport Syndrome - 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) in patients with Alport syndrome. These genes encode the assembly of collagen IV α345 scaffolds, the major constituent of the GBM. The pathogenic variants lead to a broad array of clinical manifestations, ranging from microscopic hematuria to end stage renal disease. The underlying mechanisms linking these variants with GBM abnormalities and renal failure remain obscure. Current therapy is limited to treatment with ACE inhibitors to slow progression and new therapies are in urgent need. How genetic variants of the α345 scaffold cause Alport syndrome remains unknown. Here, we focus on Z-variant causing Alport syndrome without loss of the α345 scaffold but rather reduction- or loss-of-function effect (hypomorph variant). We use this variant as a vanguard to decipher the pathogenic mechanism of the α345 collagen IV in Alport GBM and develop new forms of therapy. In Aim 1, we will utilize a new Z-variant animal model to understand mechanisms of α345 collagen IV dysfunction. In Aim 2, we will determine exact defects caused by Z-variant and similar pathogenic variants at protein and cellular levels to identify specific targets for small molecule therapies. In Aim 3, we will test protein replacement therapy and screen for pharmacological chaperones correcting assembly and stability of the collagen IV α345 scaffold. The completion of the Aims will advance our knowledge about Alport pathogenesis and lay out foundation for therapy development addressing causative mechanisms in Alport syndrome.


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 = $536,850 )
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	4	5/29/2025	NON-COMPETING CONTINUATION	$536,850
														Subtotal = $536,850

Issue Date FY: 2024 ( Subtotal = $508,070 )
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	3	6/12/2024	NON-COMPETING CONTINUATION	$508,070
														Subtotal = $508,070

Issue Date FY: 2023 ( Subtotal = $542,515 )
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	001	2	5/1/2023	NON-COMPETING CONTINUATION	$542,179
2023	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	6/2/2023	NEW	$336
2023	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	1	5/1/2023	NEW	$0
														Subtotal = $542,515

Issue Date FY: 2022 ( Subtotal = $545,222 )
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	1	9/15/2022	NEW	$545,222
														Subtotal = $545,222

Grand Total All Awards = $2,132,657

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Molecular Pathobiology of Alport Syndrome

Award Number: R01DK131101

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: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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