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S-nitrosylation of extracellular matrix proteins in diabetic nephropathy

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Applicant	Tufro, Alda
E-Mail Address	alda.tufro@yale.edu
Project Title	S-nitrosylation of extracellular matrix proteins in diabetic nephropathy
CBU ID	14GHSU1426
External SubContract ID	25732-50
Diabetic Complication	Nephropathy
Funding Program Group	Pilot & Feasibility [PF2014]
Abstract	Diabetic nephropathy (ON) is the leading cause of end-stage renal disease worldwide. The factors that induce ON in -30% of diabetic patients and the molecular mechanisms leading to ON glomerular damage and renal failure are not fully understood. Protein S-nitrosylation is a redox-dependent, reversible post-translational modification that plays important roles in physiology, insulin resistance and cardiovascular disease. However, the role of protein S-nitrosylation in ON is largely unknown. We recently identified laminin S-nitrosylation in glomeruli and podocytes, and its regulation by nitric oxide (NO) and vascular endothelial growth factor A (VEGF-A). We find that laminin de-nitrosylation associates with laminin accumulation in glomerular nodules, suggesting a role in prototypical ON lesions. Excessive TGF131 and CTGF signaling are responsible for mesangial. cell proliferation and extracellular matrix expansion in human and rodent ON. We have identified potential nitrosylation sites in active TGF131 and CTGF. We propose to examine S-nitrosylation of the mature GBM laminin 521. TGFB1 and CTGF, which are key contributors to extracellular matrix accumulation and nodular glomerulosclerosis in ON. Aim 1 will evaluate laminin 521 S-nitrosylation: We will assess S-nitrosylation of each (a5, 132 and yl ) laminin chain by biotin-switch test (BST) and proximity link assay (PLA), identify nitrosylated Cys residues by mutagenesis, BST and LC/MS/MS, and evaluate a5, 132 and y1 laminin-SNO effect on laminin secretion and degradation by podocytes, and on glomerular nodule formation in advanced ON mouse models. Aim 2 will examine TFGpl and CTGF S-nitrosylation. will determine whether endogenous TGFP1 and CTGF are S-nitrosylated in mesangial cells and mouse kidneys using BSTI' and PLA, and assess S-nitrosylation influence on TGFP1 and CTGF activity, measured by mesangial cell proliferation, SMAO phosphorylation and collagen IV production. ,
Application PDF	Application Research Plan
Status	Contract Executed
Key Personnel
Salary Total Costs	45060
Supply Total Costs	15000
Equipment Total Costs	0
Travel/Other Total Costs	0
Direct Costs	60060
Indirect Costs Proposed	39940
Total Costs Proposed	100000
Total Costs Approved	100000
Start Date	10/1/2014
End Date	9/30/2015
IFO Name	Clarke, Kenechia
IFO E-Mail Address	kenechia.clarke@yale.edu
IACUC/IRB No.	999999
IACUC/IRB Institution	Yale University
Entity ID No.	060646973
Report Request Date	10/30/2015
T1D	NO

Type	Count
Invoices	9
Progress Reports	1

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Url	CBU ID	External ID	Institution	Date	Direct	Indirect	Invoice	Balance	PDF
View	14GHSU1426	25732-50	Yale University	9/4/2015	$15,401.10	-	$15,401.10	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	8/7/2015	$7,635.13	-	$7,635.13	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	7/21/2015	$7,002.99	-	$7,002.99	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	6/5/2015	$7,003.09	-	$7,003.09	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	5/7/2015	$7,002.99	-	$7,002.99	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	4/7/2015	$7,002.99	-	$7,002.99	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	3/9/2015	$7,415.25	-	$7,415.25	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	2/6/2015	$7,415.21	-	$7,415.21	$1,027.73	View PDF
View	14GHSU1426	25732-50	Yale University	11/16/2015	$33,093.52	-	$33,093.52	$1,027.73	View PDF

Author	Complete Date	Report
Tufro, Alda	3/16/2016	View Progress Report Document

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