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The role of Poly-ADP-Ribose Polymerase in angiogenesis of ischemic-diabetic wounds

Award Number: K08HL129072
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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The role of Poly-ADP-Ribose Polymerase in angiogenesis of ischemic-diabetic wounds - PROJECT SUMMARY/ABSTRACT Chronic non-healing wounds of the lower extremities due to poor perfusion from diabetes and ischemia are a major health problem in the United States and worldwide. In the United States, approximately 21 million people currently have diabetes. Twenty-five percent of them develop a chronic wound in their lifetime which could result in 71,000 major amputations and cost 25 billion dollars annually. Surgical revascularization is currently the best therapy for limb salvage but less than 40% of the patients are candidates for revascularization. Therefore, successful medical therapy to improve perfusion for limb salvage is needed but even the most current advanced therapy such as gene and stem cell therapy remain unsatisfactory. Our lab has demonstrated that PARP-1 hyperactivity causes delayed ischemic-diabetic wound healing and PARP-1 inhibition upregulates FOSL1 transcription, enhances angiogenesis and promotes wound healing. Other studies have shown that FOSL1 is a crucial protein that controls the assembly of endothelial cells into organized capillary-like tubes. Taken all together, we hypothesize that PARP-1 hyperactivity in ischemic-diabetic wounds suppresses FOSL1 transcription which in turn leads to defective angiogenesis and thus delayed wound healing. To explore this hypothesis, we propose the following aims: Aim 1: Determine the mechanisms of PARP-1 regulation of FOSL1 transcription. Aim 2: Evaluate the therapeutic effect of PARP-1 silencing and FOSL1 activation on in-vivo angiogenesis and ischemic-diabetic wound healing using endothelial-specific gain and loss of function in mice. Aim 3: Investigate the clinical relevance of PARP-1 in ischemic-diabetic wound healing in humans via an IRB-approved pilot study. The insight into how PARP-1 drives these angiostatic phenomena will potentially uncover novel therapeutic targets to enhance angiogenesis in ischemic-diabetic wounds. My career goals are to become an independently funded surgeon scientist with the expertise in diabetic angiogenesis and to translate our bench-work discovery to novel therapeutic strategies to heal chronic ischemic- diabetic wounds in the clinic. Although this proposal has been conceptualized mostly by me, it has been intensively critiqued by my mentors to assure that it is hypothesis-driven and clinically relevant. The additional training that I will receive from my mentors includes the cutting-edge technology of molecular biology, and genomic/bioinformatic analysis which will be essential for my future success as an independent investigator. In addition to providing me the advices on the scientific methodologies and the unbiased rigor of scientific data interpretation, Drs. Mishra, Miller, Seto and Wu have committed the time to meet me regularly to discuss my research progress and to provide direction for my career development. Furthermore, there are many opportunities for collaborations within the George Washington University scientific community which has a well-established research program related to cardiovascular disease and regenerative biology. I will be well positioned to compete for R01 funding after successfully completing this K08 training proposal.


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 = -$96 )
2024	2022	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	5	10/16/2023	NON-COMPETING CONTINUATION	-$96
														Subtotal = -$96

Issue Date FY: 2022 ( Subtotal = $149,475 )
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	5	12/16/2021	NON-COMPETING CONTINUATION	$149,475
														Subtotal = $149,475

Issue Date FY: 2021 ( Subtotal = $149,475 )
2021	2021	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	12/18/2020	NON-COMPETING CONTINUATION	$149,475
														Subtotal = $149,475

Issue Date FY: 2020 ( Subtotal = $149,475 )
2020	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	12/13/2019	NON-COMPETING CONTINUATION	$149,475
														Subtotal = $149,475

Issue Date FY: 2019 ( Subtotal = $149,475 )
2019	2019	THE GEORGE WASHINGTON UNIVERSITY	2121 I ST NW STE 601	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	2	12/30/2018	NON-COMPETING CONTINUATION	$149,475
														Subtotal = $149,475

Issue Date FY: 2018 ( Subtotal = $149,475 )
2018	2018	THE GEORGE WASHINGTON UNIVERSITY	2121 I ST NW STE 601	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	1	12/21/2017	NEW	$149,475
														Subtotal = $149,475

Grand Total All Awards = $747,279

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The role of Poly-ADP-Ribose Polymerase in angiogenesis of ischemic-diabetic wounds

Award Number: K08HL129072

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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