This proposal describes the career goals and research plan for Dr. Ulka Sachdev, who is an Assistant Professor of Surgery in the Division of Vascular Surgery at the University of Pittsburgh. Dr. Sachdev completed her General Surgery and Vascular Surgery training at Mount Sinai School of Medicine in New York, and has been active in basic science research throughout her training and early faculty career. Her goal is to become an independently funded surgeon-scientist, and eventually perform translational research to assist patients. This proposal culminates from four years of research on ischemia-induced angiogenesis, and the role of HMGB-1 within that phenomenon. Peripheral artery disease is a cause of significant functional disability and morbidity. With increasing severity of arterial occlusive disease in the leg, critical limb ischemia can occur resulting in amputation in up to 40% of patients with non-reconstructable disease. Further study is required to evaluate the mechanisms that promote angiogenesis in the setting of limb ischemia, in order to optimize medical treatments for patients who can not undergo surgical revascularization. Inflammation is a component of angiogenesis, and recent evidence suggests that the nuclear protein HMGB-1 which is known to play a role in mediating systemic effects of inflammation, may also be pro-angiogenic. HMGB-1 activates receptors of innate immunity, including Toll-like Receptors (TLR) 2 and 4, as well as the Receptor for Advanced Glycation End-products (RAGE). The purpose of this proposal is to evaluate the role of HMGB-1 and TLRs in promoting angiogenesis in response to ischemia. Preliminarily, Dr. Sachdev has shown that HMGB-1 enhances endothelial cell (EC) tube formation, which is an angiogenic phenotype, increases EC proliferation when coupled with hypoxic stimulus, and may be mediated by autophagy. She has also shown that antibody to HMGB-1 blocks endothelial tube formation, and results in greater muscle necrosis when given to mice that have undergone femoral artery ligation, which is a recognized model of angiogenesis. Inhibition of autophagy also disrupts endothelial tube formation. Mice deficient in TLR4 also demonstrate greater areas of muscle necrosis than controls, as do TLR2KO mice. Finally, she has shown that ischemic myocytes demonstrate loss of HMGB-1 from nuclei compared to normoxic myocytes, suggesting that tissue ischemia may lead to release of HMGB-1 into the surrounding milieu, rendering it available to mediate angiogenic events. There are three main aims of this proposal, directed at understanding the effect of HMGB-1 on both vascular cells in vitro, and ischemia-induced angiogenesis in vivo.
The first aim i s to determine the temporal relationship between autophagy and HMGB1 release during EC angiogenic behavior.
The second aim i s to determine the function of HMGB-1 and autophagy in skeletal muscle angiogenesis in vivo.
The third aim i s to identify a role for the TLRs in mediating the angiogenic actions of HMGB1.

Public Health Relevance

The following proposal aims to elucidate if the danger signal HMGB-1 which is released by necrotic or stressed cells, as well as its receptors, helps promote the formation of new blood vessels through the process of angiogenesis in the setting of tissue ischemia. This project will help understand the mechanisms that govern neovascularization, and may help patients with peripheral vascular disease who can not undergo revascularization by bypass or endovascular therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-K (O1))
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Scott, Jane
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University of Pittsburgh
Schools of Medicine
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Xu, Jun; Cui, Xiangdong; Li, Jiehua et al. (2018) Chloroquine improves the response to ischemic muscle injury and increases HMGB1 after arterial ligation. J Vasc Surg 67:910-921
McEnaney, Ryan M; Shukla, Ankur; Madigan, Michael C et al. (2016) P2Y2 nucleotide receptor mediates arteriogenesis in a murine model of hind limb ischemia. J Vasc Surg 63:216-25
Sachdev, Ulka; Cui, Xiangdong; Xu, Jia et al. (2014) MyD88 and TRIF mediate divergent inflammatory and regenerative responses to skeletal muscle ischemia. Physiol Rep 2:
Sachdev, Ulka; Cui, Xiangdong; Tzeng, Edith (2013) HMGB1 and TLR4 mediate skeletal muscle recovery in a murine model of hindlimb ischemia. J Vasc Surg 58:460-9