This postdoctoral fellowship project aims to determine whether specialized pro-resolving lipid mediators (SPM) promote the resolution of inflammation and increase perfusion and tissue regeneration in the setting of skeletal muscle ischemia. Currently, there are no specific non-surgical therapeutic agents available to promote revascularization in diseases associated with impaired tissue perfusion and wound healing, such as diabetes and peripheral artery disease (PAD). Further, several therapeutic strategies designed to promote revascularization have limited efficacy, in part because they can exacerbate inflammation. Therefore, new approaches are needed that increase revascularization and tissue regeneration, while decreasing inflammation. Resolvins are a novel family of SPM that blunt the production of pro-inflammatory mediators and promote macrophage phagocytosis of apoptotic cells. Recently, we found that resolvins increase revascularization during hind limb ischemia (HLI), suggesting they may be an entirely new class of mediators that resolve inflammation while promoting revascularization. Our working hypothesis is that monocytes infiltrate ischemic tissue and generate SPM, which in turn facilitate revascularization during HLI by promoting a wound healing macrophage phenotype. To test this hypothesis, we will determine the contribution of monocytes to resolvin biosynthesis and assess the endogenous receptor-mediated roles of resolvins in revascularization. We will determine whether monocytes and macrophages are prominent cellular targets of resolvins during revascularization. Lastly, we will establish whether resolvins promote revascularization in mice with chronic inflammation. In order to perform these studies, extensive hands-on training in state-of-the-art mass spectrometry-based methods is proposed in combination with advanced instruction in immunology, bioinformatics and biostatistics. A mentoring team of highly accomplished basic scientists and clinicians will assist in the scientific direction of the project and the career development of the applicant. Completion of these studies will provide fundamental new insights into the biological actions of resolvins and could lead to the development of a new class of therapeutics to resolve inflammation and increase tissue perfusion and repair in patients with PAD or diabetes.
Results of this project will provide a new understanding of the mechanistic basis whereby resolvins promote revascularization and tissue regeneration during ischemia. These studies could lead to the development of new therapeutics aimed at simultaneously resolving inflammation and increasing tissue repair.
| Gromovsky, Anthony D; Schugar, Rebecca C; Brown, Amanda L et al. (2018) ?-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators. Arterioscler Thromb Vasc Biol 38:218-231 |
| Hellmann, Jason; Sansbury, Brian E; Wong, Blenda et al. (2018) Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair. J Invest Dermatol 138:2051-2060 |
| Wu, Bian; Werlin, Evan C; Chen, Mian et al. (2018) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 68:188S-200S.e4 |
