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BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle

Award Number: R01DK120866
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: 09/19/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle - Project Summary The development and progression of diabetes involves oxidative stress and inflammation that leads to disorders in multiple organs including the cardiac and skeletal muscle. However, it remains unknown whether inflammation induced cell death, known as pyroptosis occurs in cardiac and skeletal muscle of diabetics. Our preliminary data shows that diabetic mice have enhanced infiltration of monocytes, pro-inflammatory toll-like receptor 4, NLRP3 inflammasome, activated caspase-1 and increased pro-inflammatory cytokines in the heart as well as skeletal muscle. Treatment with the recombinant bone morphogenic protein-7 (BMP-7) decreased hyperglycemia, inflammation and improved cardiac and muscle function. Based on these preliminary data, we hypothesize that BMP-7 increases anti-inflammatory M2 macrophages decreases pyroptosis, thereby improving cardiac and skeletal muscle function in diabetes. We propose to test this hypothesis through the following aims. 1: Diabetes causes cardiac and skeletal muscle dysfunction through increase of inflammatory cytokines, activation of NLRP3 inflammasome and caspase 1 regulated pyroptosis. 2: Treatment with BMP-7 differentiates monocytes into anti-inflammatory M2 macrophages resulting in amelioration of pyroptosis and adverse cardiac and skeletal muscle remodeling in diabetic mice. 3: Chronic treatment with BMP-7 ameliorates diabetic complications through suppression of inflammatory pathways and pyroptosis in a translational rabbit model of diabetes. The proposed studies will be carried out in the well-established models of Type 1 and Type 2 diabetes. We expect to elucidate the critical role of pyroptosis in causing cardiac and skeletal muscle dysfunction and the beneficial role of BMP-7 therapy in diabetes. These studies have the promise for critical care of diabetic patients, because BMP-7 is clinically approved for the treatment of osteoporosis patients in Europe.


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: 2024 ( Subtotal = $0 )
2024	2021	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $965,078 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	9/3/2021	NON-COMPETING CONTINUATION	$586,966
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/27/2021	SUPPLEMENT FOR EXPANSION	$157,549
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/6/2021	SUPPLEMENT FOR EXPANSION	$220,563
2021	2020	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $965,078

Issue Date FY: 2020 ( Subtotal = $586,966 )
2020	2020	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/19/2020	NON-COMPETING CONTINUATION	$586,966
														Subtotal = $586,966

Issue Date FY: 2019 ( Subtotal = $586,966 )
2019	2019	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/15/2019	NON-COMPETING CONTINUATION	$586,966
														Subtotal = $586,966

Issue Date FY: 2018 ( Subtotal = $596,683 )
2018	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2018	NEW	$596,683
														Subtotal = $596,683

Grand Total All Awards = $2,735,693

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BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle

Award Number: R01DK120866

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: 09/19/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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