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.
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. PARP-1 hyperactivity causes impaired angiogenesis and delays ischemic-diabetic wound healing but the exact mechanism has not been well established. This proposal elucidates the molecular mechanism underlying PARP-1 regulation FOSL1 transcription in angiogenesis in order to discover novel therapeutic targets to enhance angiogenesis and promote ischemic-diabetic wound healing.
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