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Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

Award Number: R01HL149704
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease - PROJECT SUMMARY/ABSTRACT Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s) are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes). We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR) which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno- associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD. Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to treat a patient population that currently has few available options.


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 = $588,983 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	11/8/2023	NON-COMPETING CONTINUATION	$540,903
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	5	6/24/2024	NON-COMPETING CONTINUATION	$48,080
														Subtotal = $588,983

Issue Date FY: 2023 ( Subtotal = $585,948 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$527,353
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	4	2/11/2023	NON-COMPETING CONTINUATION	$58,595
														Subtotal = $585,948

Issue Date FY: 2022 ( Subtotal = $584,514 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	3	6/8/2022	NON-COMPETING CONTINUATION	$58,452
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	3	11/5/2021	NON-COMPETING CONTINUATION	$526,062
														Subtotal = $584,514

Issue Date FY: 2021 ( Subtotal = $580,161 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$58,016
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	11/20/2020	NON-COMPETING CONTINUATION	$522,145
														Subtotal = $580,161

Issue Date FY: 2020 ( Subtotal = $535,536 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	1	11/29/2019	NEW	$535,536
														Subtotal = $535,536

Grand Total All Awards = $2,875,142

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Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

Award Number: R01HL149704

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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