Nicholas Ernst Smit Sibinga, M.D.
Areas of Investigation
Dr. Nicholas Sibinga uses genetic approaches to study vascular remodeling, a complex biological response to changes in hemodynamics, metabolism, local and systemic inflammation, and physical injury. His lab has found that expression of the large cadherin Fat1 increases markedly in smooth muscle cells after vascular trauma and has significant effects on vascular smooth muscle growth and migration, which are key components of the remodeling process (Hou et al. J Cell Biol, 2006. 173: 417-429).
- Characterization of the cell autonomous signals mediated by the Fat1 cytoplasmic domain, which depend on interactions with b-catenin, Ena/VASP, and atrophins
These interactions point to roles for Fat1 in regulating cell growth, motility, and polarity during the response to vascular injury. In addition, because global Fat1 inactivation causes perinatal death, a conditionally targeted Fat1loxP mouse has been generated. This mouse will be used to evaluate the importance of Fat1 in post-natal vascular remodeling in vivo.
- Transplant arteriosclerosis, the major limitation to long-term success of solid organ transplantation
In a collaborative effort with Dr. Richard Stanley, the Sibinga lab has shown that the cell surface isoform of colony stimulating factor-1 (CSF-1) in both donor and recipient tissues is required for transplant arteriosclerosis. These studies, performed by arterial transplantation in genetically modified mice expressing discrete CSF-1 isoforms, suggest the importance of an autocrine-juxtacrine CSF-1 signaling loop for growth and survival of smooth muscle cells that express the CSF-1 receptor./ This discovery has distinct implications for therapeutic approaches to transplant arteriosclerosis.
- In vivo role of allograft inflammatory factor-1 (Aif-1), a macrophage-specific Ca2+-binding, EF-hand protein, that is upregulated in multiple models of vascular remodeling and inflammation, including transplant arteriosclerosis, vascular injury, and atherosclerosis
Aif-1 induction has been linked to increased cytokine production and enhanced growth and survival in vitro, but its importance in vivo remains unclear. Aif-1 knockout mice have been generated and are being studied in transplant arteriosclerosis and atherosclerosis models.