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C-KIT SIGNALING IN COLLATERALS REMODELING

Award Number: K01HL145359
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/17/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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C-KIT SIGNALING IN COLLATERALS REMODELING - TITLE: C-KIT SIGNALING IN COLLATERALS REMODELING Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease. At the moment, endovascular procedures and bypass surgeries are the only effective treatments for limb revascularization. However, a significant proportion of CLI patients are not good candidates for these interventions, requiring primary amputation as the main treatment option. Therefore, an effective pharmacological strategy that prevents CLI and its devastating consequences represents a much- needed alternative for this patient population. Arteriogenesis is a physiological compensatory process in which pre-existing collaterals enlarge and serve as natural bypasses to severe occlusion of arteries. We have recently identified that the c-Kit receptor tyrosine kinase plays a key role in the remodeling of collaterals during arteriogenesis. We found that defective c-Kit function compromises blood flow recovery after hindlimb ischemia, which was not resolved with hematopoietic reconstitution of c-Kit activity. We have confirmed defective arteriogenesis in c-Kit mutant mice compared to controls. Mechanistically, we advanced our understanding of how the c-Kit/Kruppel-like factor 4 (KLF4) pathway orchestrates collateral remodeling. Therefore, our central hypothesis is that c-Kit/KLF-4 signaling controls the recovery of the smooth muscle cell (SMC) contractile phenotype at the maturation phase of arteriogenesis to prevent excessive remodeling and narrowing of collaterals. We propose two Specific Aims (SA) to test our hypothesis. In SA1, we will demonstrate the involvement of vascular c-Kit signaling in arteriogenesis. We will investigate whether inactivation or activation of c-Kit specifically in SMCs will lead to dysfunction or optimal arteriogenesis in unique transgenic models of loss- and gain- of-function of c-Kit, respectively. We will also identify molecular mechanisms that can be altered by the loss- or gain-of-function on SMC c-Kit. In SA2, we will dissect the molecular pathways upstream and downstream of c-Kit in SMCs. First, we will investigate whether cyclic strain dictates the oscillatory expression of the c-Kit receptor by activating protein kinase C, leading to c-Kit suppression. Next, we will determine whether c-Kit inhibits KLF4 through FBXO32-mediated ubiquitination, thereby restoring the contractile SMC phenotype and preventing defective remodeling. RELEVANCE: Approximately 80,000 major lower-extremity amputations occur in the United States every year due to CLI. In this study, we will identify novel therapeutic targets to improve arteriogenesis and prevent or alleviate the devastating effects of CLI. Moreover, we will identify the molecular mechanism that dictates phenotypic switching in SMCs, which may be applicable to the understanding and treatment of other vascular occlusive diseases.


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 = -$566 )
2024	2023	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	5	4/19/2024	NON-COMPETING CONTINUATION	-$566
														Subtotal = -$566

Issue Date FY: 2023 ( Subtotal = $126,368 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	5	1/13/2023	NON-COMPETING CONTINUATION	$126,368
														Subtotal = $126,368

Issue Date FY: 2022 ( Subtotal = $126,368 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	4	2/7/2022	NON-COMPETING CONTINUATION	$126,368
														Subtotal = $126,368

Issue Date FY: 2021 ( Subtotal = $126,368 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	3	12/23/2020	NON-COMPETING CONTINUATION	$126,368
														Subtotal = $126,368

Issue Date FY: 2020 ( Subtotal = $126,368 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	2	1/17/2020	NON-COMPETING CONTINUATION	$126,368
														Subtotal = $126,368

Issue Date FY: 2019 ( Subtotal = $126,368 )
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	1	1/17/2019	NEW	$126,368
														Subtotal = $126,368

Grand Total All Awards = $631,274

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C-KIT SIGNALING IN COLLATERALS REMODELING

Award Number: K01HL145359

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/17/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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