Peripheral artery disease causes significant functional disability and can result in limb loss in a significant proportion of patients who are not candidates for surgical revascularization. Thus efforts have been made to optimize conditions to enhance angiogenesis in ischemic tissue and help improve limb preservation rates. This is an area of active investigation that includes the administration of single agents, to treatment with multicellular compounds injected directly into the ischemic leg. Most of the therapies that are proposed for patients with critical limb ischemia who have limited bypass or endovascular options are aimed at improving angiogenesis. However, stimulating muscle regeneration and functionality are also important goals.
The innate immune system, characterized by highly conserved pattern-recognition receptors (PRR) such as the toll-like receptors (TLRs), is an attractive system to study in angiogenesis and muscle regeneration. Danger signals released by stressed tissues can serve as important mediators of inflammation, as well as repair. We have shown that the nuclear protein High Mobility Group Box 1 (HMGB1), a mediator of end organ damage in times of physiologic stress, can also promote angiogenic behavior in endothelial cells. We have also shown that HMGB1 as well as Toll-like receptor signaling may be critically important for ischemic muscle recovery.
Our laboratory focuses on the roles of HMGB1as well as Toll-like receptor signaling in mediating angiogenesis and muscle recovery in the setting of ischemia. The ultimate goal is to determine the ways these systems can be manipulated to eventually help create therapeutics for patients with critical limb ischemia. The lab has hosted medical students as well as residents and postdocs.
Publications from the Sachdev Lab can be viewed through PubMed.