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Epigenetic and Transcriptional Regulation of Angiogenic Regulator CD36 and Transformation of Capillaries into Small Arteries

Award Number: R01HL136423
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Arteriolar differentiation and formation of small arteries from very tiny blood vessels (capillary arterialization) are fundamental processes underlying ischemic organ recovery from a noxious insult. Despite its obvious clinical and biological importance, little is known about the molecular mechanisms of these events and their regulation. We have recently discovered that transcriptional repression of CD36 is involved in a proangiogenic and proarteriogenic reprogramming of capillary endothelial cells (EC) or microvascular EC (MVECs), and is implicated in capillary arterialization. Specifically, we have shown that LPA/PKD-1 signaling-mediated CD36 transcriptional repression plays a key role in promoting arteriogenic gene expression in MVECs, and microvascular remodeling in vivo. Moreover, EC-specific deletion of pkd-1 showed impaired recovery from ischemic insult. These unexpected findings led to the hypothesis that CD36 gene repression via LPA/PKD-1 signaling axis reprograms MVECs to differentiate into arteriolar ECs and promotes capillary arterialization. To test this hypothesis, we have established two- and three-dimensional MVEC culture systems, and in vivo Matrigel assays. More importantly, we have established hindlimb ischemia models in unique cd36 gene deficient mice with the EC-specific translating ribosome affinity purification (TRAP), and EC-specific pkd-1 deficient mice or EC-specific pkd-1 deficient TRAP mice. These novel TRAP transgenic lines have targeted gene deficiency and carry an EC-specific EGFP-tag that allows us to directly purify ribosome-bound mRNA from ECs in vivo for next generation RNA-sequencing, facilitating probes of EC-specific transcriptome and ribosome binding of noncoding RNAs. The availability of this mouse model provides us for the first time with the ability to devise experiments to gain new and fundamental insights into biology of adult arteriolar growth under ischemic conditions. Using these tools,, we aim to 1) prove that in MVECs the LPA/PKD-1-CD36 signaling axis is essential to regulate MVEC reprogramming and arteriolar differentiation; 2) test the hypothesis that CD36 transcriptional repression via the LPA/PKD-1-FoxO1 signaling axis is a critical component of a genetic reprogramming switch to promote capillary arterialization (de novo arteriogenesis). Together with assays using a series of molecular biology and imaging methods single cell RNA-sequencing as well as zebrafish models, we expect to accomplish these aims and provide a comprehensive evaluation of arteriolar differentiation and capillary arterialization. This will illuminate poorly explored and poorly understood aspects of vascular biology. This proposal focuses on de novo arteriogenesis in adult because of its remarkably practical significance. Getting a greater understanding of capillary arterialization in adult tissues will provide important insights into finding novel and effective therapeutic targets against ischemic heart and vascular 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: 2022 ( Subtotal = -$29,613 )
2022	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	5/26/2022	NON-COMPETING CONTINUATION	-$29,613
														Subtotal = -$29,613

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	7/10/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,754 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	004	3	3/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$665,462
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	2/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$371,754
2019	2018	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	2/5/2019	NON-COMPETING CONTINUATION	$0
2019	2018	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	003	2	3/8/2019	NON-COMPETING CONTINUATION	-$416,347
2019	2017	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	002	1	3/8/2019	NEW	-$249,115
														Subtotal = $371,754

Issue Date FY: 2018 ( Subtotal = $416,347 )
2018	2018	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	001	2	6/23/2018	NON-COMPETING CONTINUATION	$8,328
2018	2018	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	2/24/2018	NON-COMPETING CONTINUATION	$408,019
														Subtotal = $416,347

Issue Date FY: 2017 ( Subtotal = $432,129 )
2017	2017	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	5/31/2017	NEW	$432,129
														Subtotal = $432,129

Grand Total All Awards = $1,561,867

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Epigenetic and Transcriptional Regulation of Angiogenic Regulator CD36 and Transformation of Capillaries into Small Arteries

Award Number: R01HL136423

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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