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Role of fibrate mechanism in diabetes and its complications

Award Number: R15DK085496
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: 06/01/2010
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Role of fibrate mechanism in diabetes and its complications - Project Summary/Abstract: The overall aim of this proposal is to understand the fibrate mechanism of action in diabetes and its complications. Our studies demonstrate that 1) fenofibrate is most potent among all the fibrates tested in inhibiting aldose reductase (AR) activity in vitro; 2) fenofibric acid shows less potency in inhibiting AR catalyzed forward reaction and only in the pH range 5.0- 6.0 unlike fenofibrate; and 3) first structure and binding proof affirms that AR is a drug target for fibrate derivative, WY 14,643. Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to its active metabolite, fenofibric acid. Unchanged fenofibrate (prodrug) has been reported to be undetectable in plasma samples following an oral dose. Fibrates are successful in the treatment of hypertriglyceridaemia or mixed hyperlipidaemia. On the other hand AR is known to play a significant role in diabetes and its complications and numerous attempts to identify inhibitors for the treatment of AR mediated complications have not proven successful. Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) which may modify AR by oxidizing Cys residues to sulfenic acids and the sulfenic acid modified AR shows higher enzyme activity. The objective of this proposal is to evaluate the role of fibrate derivatives in the function of wild-type and C298X mutant AR. The SPECIFIC AIMS are 1) determine the inhibition potency and molecular interactions of fenofibrate derivatives; 2) establish the role of Cys298 in AR enzyme activity in the presence of newly synthesized fenofibrate derivatives, and 3) evaluate the function of the Cys298 modified AR in the presence of fibrate derivatives. The project will combine chemical, biochemical (spectrofluorometric enzymatic assays) and molecular (structural methods) approaches with the use of recombinant and cell culture samples. We expect that the results obtained from these studies will further our understanding of the nature of fibrate mechanism under normal and high glucose conditions.


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: 2022 ( Subtotal = -$85,967 )
2022	2017	YOUNGSTOWN STATE UNIVERSITY	1 UNIVERSITY PLAZA	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	9/27/2022	COMPETING CONTINUATION	-$85,967
														Subtotal = -$85,967

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	YOUNGSTOWN STATE UNIVERSITY	1 UNIVERSITY PLAZA	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/30/2021	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $288,600 )
2017	2017	YOUNGSTOWN STATE UNIVERSITY	1 UNIVERSITY PLAZA	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/25/2017	COMPETING CONTINUATION	$288,600
														Subtotal = $288,600

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2010	YOUNGSTOWN STATE UNIVERSITY	410 WICK AVENUE	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/18/2014	NEW	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $202,275 )
2010	2010	YOUNGSTOWN STATE UNIVERSITY	410 WICK AVENUE	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/14/2010	NEW	-$9,525
2010	2010	YOUNGSTOWN STATE UNIVERSITY	410 WICK AVENUE	YOUNGSTOWN	OH	44555	MAHONING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/17/2010	NEW	$211,800
														Subtotal = $202,275

Grand Total All Awards = $404,908

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Role of fibrate mechanism in diabetes and its complications

Award Number: R15DK085496

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: 06/01/2010

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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