Object moved

Protease-activated receptors in diabetic complications

Summary

Data Summary

Applicant	Takahashi, Nobuyuki
E-Mail Address	nobuyuki.takahashi.a8@tohoku.ac.jp
Project Title	Protease-activated receptors in diabetic complications
CBU ID	16GRU3676
External SubContract ID	30835-14
Diabetic Complication	Nephropathy
Funding Program Group	Pilot & Feasibility [PF2016] Preclinical
Abstract	Diabetic nephropathy is a leading cause of renal failure and is a major life-threatening problem. Although pharmacological inhibition of the renin-angiotensin system slows progression of diabetic nephropathy, patient prognosis remains poor. We have clarified that lack or reduced expression of endothelial nitric oxide synthase (eNOS, Nos3) exacerbates diabetic nephropathy, which is associated with increased expression and activity of renal tissue factor (TF), an initiator of the coagulation cascade. Anti-TF neutralizing antibody reduced inflammation in diabetic nephropathy. Coagulation proteases contribute to tissue injury mediated by protease-activated receptors (PARs). PAR2 is activated by TF- coagulation factor VIIa (FVIIa) complex and coagulation factor Xa (FXa) and up-regulates inflammation and fibrosis. Most recently we reported that lack of PAR2 are protective against diabetic nephropathy. Interestingly, these mice have reduced PAR1 expression in the kidney. Both PAR1 and PAR2 are proinflammatory, and PAR1 is known to be increased in diabetic kidneys. Accordingly, PAR2 and possibly PAR1 are promising target for diabetic complications. Specific Aim 1 will clarify whether inhibiting both PAR1 and PAR2 is more effective in preventing diabetic nephropathy than inhibiting PAR2 alone. We generate male mice lacking PAR2 (F2rl1-/-) or having wild type PAR2 (F2rl1+/+) on Nos3+/- and Ins2Akita/+ background. These mice will be divided into two groups and treated or not treated with PAR1 specific antagonist E5555. Specific Aim 2 will identify chemical compounds with PAR2 inhibiting properties. PAR2 antagonists will be screened using several chemical compound libraries. We add library compounds and calcium sensitive dye Fluo4 to human endothelial cell line EA.hy926, and look for compounds that inhibit the increase in intracellular calcium by a PAR2 agonist peptide 2f-LIGRLO. Selectivity of the compounds for PAR2 and PAR1 will be evaluated by inhibition of the increase in intracellular calcium by a PAR1 agonist.
Application PDF	Application Research Plan
Status	Contract Executed
Key Personnel
Salary Total Costs	6000
Supply Total Costs	31000
Equipment Total Costs	15000
Travel/Other Total Costs	25000
Direct Costs	77000
Indirect Costs Proposed	23000
Total Costs Proposed	100000
Total Costs Approved	100000
Start Date	10/1/2016
End Date	9/30/2017
IFO Name	Fujisawa, Kousuke
IFO E-Mail Address	ph-som@grp.tohoku.ac.jp
IACUC/IRB No.	2016PhA-011
IACUC/IRB Institution	Tohoku University
Entity ID No.
Report Request Date	11/30/2017
T1D	NO

Type	Count
Invoices	2
Progress Reports	1
Experiments	1

Data Submission

Add Experimental Data

Url	CBU ID	External ID	Institution	Date	Direct	Indirect	Invoice	Balance	PDF
View	16GRU3676	30835-14	Tohoku University	5/24/2017	$9,491.76	$759.34	$10,251.10	-	View PDF
View	16GRU3676	30835-14	Tohoku University	1/18/2018	$82,913.48	$6,835.42	$89,748.90	-	View PDF

Author	Complete Date	Report
Takahashi, Nobuyuki	11/17/2017	View Progress Report Document

Display Stats

OrderID	Investigator	Experiment	Species	Status	Measurements
0	Nobuyuki Takahashi	Protease-activated receptors in diabetic complications	M. musculus	Completed	0

Click here to cancel and return to funding program application

*Author:
*SubContract:
*Select File:	Click browse and select the file to upload. (Please upload ONLY TXT, Image Files (not histolgy), PDF, XLS, XLSX, DOC, or DOCX files.)

看片视频

Object moved to here.

看片视频