MD/PhD Program

Additional Training
Picower Institute for Medical Research

Summary of Research Interests
Dr. Mitchell's laboratory work is primarily concentrated on characterizing the identity and mechanisms of novel polypeptide and lipid growth factors as they contribute to cancer progression. The primary focus at present is the investigation of the pro-inflammatory cytokine, migration inhibitory factor (MIF), as it pertains to de novo and carcinogen-mediated tumorigenesis. Recent studies from the laboratory reveal a critical role for MIF in the modulation of cell cycle regulatory pathways central to oncogene-mediated malignant transformation and neoplastic progression. As such, there are three fundamental areas of active investigation focusing on this unique molecule:

1) Cell Biology Recent experimental findings have suggested the existence of several cell signaling pathways and transcriptional regulators that may be influenced by MIF action. Laboratory members are currently examining the precise contribution of MIF to Rho GTPase-dependent cyclin D1 expression and the subsequent inactivation of the retinoblastoma tumor suppressor in cancers. The hope is that the identification of the signaling effectors responsible for these MIF-dependent effects will provide clues into how MIF functionally acts at the plasma membrane of target cells.

2) Translational Several in vivo models of tumorigenesis are currently being established in the laboratory that will seek to determine the precise role of MIF in the development of several different human malignancies. For instance, mice that have a functionally inactive MIF gene are being backcrossed against mice that spontaneously form tumors of the breast, colon, lung or skin. By comparing tumor development in these mice to tumor formation in mice with intact MIF Dr. Mitchell hopes to identify the precise contribution of MIF to different types of cancers.

3) Biochemistry and enzymology of MIF The mechanism for how MIF acts at the cell surface to relay signals to interior compartments of the cell is largely unresolved. Interestingly, MIF possesses a unique, non physiologic catalytic activity as a D-dopachrome tautomerase. While controversial, the idea that MIF's mechanism of action may be a result of its catalytic action on an as yet, undefined substrate, is intriguing. Dr. Mitchell's laboratory has recently discovered a physiologic substrate for MIF that may help to explain its bio-functions and the laboratory is now actively investigating this possibility in greater detail. Finally, in collaboration with Dr. John Trent of the JG Brown Cancer Center, molecular modeling of the catalytic active site of MIF is being used to rationally design small molecule inhibitors of MIF in the hopes of discovering novel anti-inflammatory and anti-cancer chemotherapies.

Telephone: 502-852-7698
Fax: 502-852-3799
Email: ramitc04@gwise.louisville.edu