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High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes

Award Number: R01DK119656
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT Insulin resistance (IR) in skeletal muscle and other tissues is obligatory for the development of type 2 diabetes. Excess accumulation of incompletely oxidized non-esterified fatty acids (FAs) in muscle cells, i.e., lipotoxicity, is increasingly appreciated to underlie the development of IR. In parallel, branched chain amino acids (BCAAs) have recently moved front and center in the field of diabetes, as unbiased metabolomic profiling in large prospective epidemiological studies has shown that serum elevations of BCAAs predict IR and diabetes as much as 20 years prior to clinical presentation. We have now uncovered a novel molecular pathway that links these two observations. Active catabolism of the BCAA valine in skeletal muscle causes the paracrine secretion of a metabolite, 3-hydroxyisobutyrate (3-HIB), which promotes entry of FAs into skeletal muscle, and subsequent lipotoxicity. The identification of this pathway provides a novel entry point for the potential treatment of insulin resistance, orthogonal to most current insulin-based or insulin secretogenic therapies. The proposed project responds to PA-16-374 (Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK) and will identify lead-enabling small molecules that target this newly discovered pathway. Aim 1 use in silico and high-throughput screening to identify molecules that block production of 3HIB. Identified hits will be taken through a robust workflow of secondary counterscreens. In Aim 2, the molecules identified in Aim 1 will be tested for efficacy and safety in intact cells. In Aim 3, validated hits from Aims 1 and 2 will first be submitted to in vivo pharmacokinetic and pharmacodynamic studies. Viable candidates will then be tested for their ability to block lipid accumulation and insulin resistance in 3HIB-treated mice as well as in a pre- clinical high-fat fed model of insulin resistance. The proposed work represents a close collaboration between academia and a strong private sector team with a long history of successes. We propose a novel and provocative hypothesis, and a previously unexplored approach to understand and target lipotoxicity. Success would yield novel targets and potential lead compounds for the development of new therapeutics that address the root of insulin resistance.


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 = -$1,253 )
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/30/2023	NON-COMPETING CONTINUATION	-$1,253
														Subtotal = -$1,253

Issue Date FY: 2023 ( Subtotal = -$747,631 )
2023	2020	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/13/2023	NON-COMPETING CONTINUATION	-$625,517
2023	2019	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/13/2023	NEW	-$122,114
														Subtotal = -$747,631

Issue Date FY: 2022 ( Subtotal = $655,774 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/29/2021	NON-COMPETING CONTINUATION	$590,197
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/24/2022	NON-COMPETING CONTINUATION	$65,577
														Subtotal = $655,774

Issue Date FY: 2021 ( Subtotal = $661,283 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$661,283
2021	2020	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/4/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $661,283

Issue Date FY: 2020 ( Subtotal = $625,517 )
2020	2020	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/10/2020	NON-COMPETING CONTINUATION	$62,553
2020	2020	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/24/2020	NON-COMPETING CONTINUATION	$562,964
														Subtotal = $625,517

Issue Date FY: 2019 ( Subtotal = $632,099 )
2019	2019	ICAGEN-T, INC.	2090 E INNOVATION PARK DR	ORO VALLEY	AZ	85755	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/27/2019	NEW	$632,099
														Subtotal = $632,099

Grand Total All Awards = $1,825,789

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High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes

Award Number: R01DK119656

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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