Biochemistry; Biology; Biomedical Engineering; Immunogenetics
Skin Diseases Research Center, Yale
WHRY Pilot Project Program Investigators
To characterize the development and function of regulatory T cells and characterize mechanisms that affect cancer, autoimmunity, inflammation, transplantation and recruitment into vascular sites.
Extensive Research Description
research goals of the lab are to characterize the development and function of
regulatory T cells and characterize mechanisms that affect autoimmunity,
inflammation, transplantation and recruitment into vascular sites. Both mouse and human responses are
studied in vitro and in vivo which includes the development and use of
humanized mice. In addition, our
experience with synthetic microvessels has lead to a translational project to
revascularize islets to treat type I diabetes.
Specific accomplishments in the last year:
- PPARs: Peroxysome proliferated activated receptors (PPARs) represent a group of transcription factors that are critical in regulating glucose and lipid metabolism. Ligands of PPARg inhibit metabolically induced arteriosclerosis and also prevent the development of inflammatory disorders in several experimental mouse models including EAE, asthma, rheumatic arthritis and sepsis. The role of PPARg in graft arteriosclerosis (GA) has not been characterized. We therefore tested the in vivo effects of administration of the endogenously occurring ligand, 15 deoxy-prostaglandin-J2 (15-d-PGJ2), and ciglitazone and pioglitazone on vascular remodeling of human artery induced by alloreactive PBMC and the IFN-g model. The data indicate that 15-d-PGJ2 and pioglitazone significantly inhibit human GA in our in vivo human arterial graft model in immunodeficient mice. These effects appear specific because they are reversed by treatment with an antagonist, GW9662. Preliminary results suggest that it is possible to reverse disease once it is established for 3 weeks in this model.
- Microorgan Islet Grafts: The goal of this project is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. Casting the islets together with EC in collagen gels effectively revascularizes the islets in SCID/bg mice. Indeed, our pilot data indicate that these human islet-EC microorgans secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests. We are characterizing the structure/function properties of these microorgans in detail, including the microvessel structure and the stability of the microvessels with time. During the last year we (with Serge Kobsa and M. Saltzman) are characterizing new nanospheres that have a greater capacity to secrete factors for longer periods of time. We have shown that Hepatocyte Growth Factor (HGF) has significant anti-apoptotic activity on islets in vitro and hope to evaluate this with the new delivery systems in vivo. Inflammation and Colon Cancer: The APC/Min mouse is a highly studied model of intestinal tumorigenesis. During the last year we have shown that APC/Min mice that are deficient in the proinflammatory cytokine IL-17A have a 90% reduction in small intestinal polyps. We hope to define both the source of the IL-17A that is critical as well as the cell type that is the target of this cytokine.
- Viehmann Milam, A.A., Maher, S.E., Gibson, J.A., Lebastchi, J., Wen, L., Ruddle, N.H., Herold, K.C. and Bothwell, A.L.M. (2014). A Humanized Mouse Model of Autoimmune Insulitis. Diabetes, 63:1712-1724.
- Kidane, D., Chae, W.J., Czochor, J., Eckert, K.A., Glazer, P.M., Bothwell, A.L.M., Sweasy, J.B. (2014). Links between DNA repair and inflammation. Crit. Rev. Biochem. Mol. Biol., 49:116-139.
- Immunity 44: 246-258.
- Park, H.-J., Choi, J.-Y., Senejani, A.G., Tobiasova, Z., Kim, D.-H., * Bothwell, A.L.M. and * Choi, J.-M., (2014).The nuclear receptor PPAR? regulates T cell tolerance and germinal center formation via follicular helper T cells. PLoS ONE 9(6): e99127. *joint senior authors.
- Int. J. Mol..Sci., 17:1347-1357; doi:10.3390/ijms17081347
- Senejani, A., Liu, Y., Kidane, D., Maher, S.E., Zeiss, C.J., Park, H.-J., Kashgarian, M., McNiff, J.M., Bothwell, A.L.M. and Sweasy, J.B. (2014). Mutation of DNA Polymerase Beta Results in Lupus, Cell Reports 6:1-8. PMCID: PMC3916967.