Clifford Steer, M.D.

Contact Information Phone: 612-625-8999 Fax: 612-625-5620 Email: steer001@umn.edu Address: Dept. of Medicine GI Division, MMC 36 420 Delaware St., S.E. Minneapolis, MN 55455

Dr. Steer received his B.A. in Physiology/Chemistry and M.D. at the University of Minnesota in Minneapolis. He completed an Internal Medicine Residency at the University of Minnesota Medical Center in Minneapolis. Dr. Steer accepted a Hepatology Fellowship at the NIH in the Section on Diseases of the Liver and remained on staff at the NIH as an Expert in his field for an additional 10 years. In 1989, Dr. Steer joined the University of Minnesota as a Professor in the Department of Medicine, Genetics and Cell Development.

During his time at the University, Dr. Steer has been active in mentorship of PhD students and post-doctoral fellows in his lab, is a member of multiple committees and has continued to be academically productive in his current area of research.

Research Interests

My laboratory has been involved in three major areas of research during the last five years. The Sleeping Beauty (SB) transposon system functions via a cut-and-paste mechanism catalyzed by the binding of SB transposase to inverted repeats/direct repeats (IR/DRs) of the mariner transposon. It excises the relevant transgene from the transposon at the IR/DRs and inserts the element into random TA dinucleotide sites within the genome. This transposon technology is as powerful as any traditional gene therapy but functions without the use of potentially harmful viral vectors. We are applying SB to a variety of different animal disease models, including liver, bone marrow and brain disorders. Several of our projects involve ex vivo gene therapy of somatic cells, including blood outgrowth endothelial cells, and a variety of adult stem cells. We have already constructed the next generation of SB constructs containing both inhibitor sequences (RNAi) and transgenes, thus providing long-term interference of the mutant proteins and expression of their wild-type sequences. My laboratory is also interested in characterizing the effects of SB transposition on genomic methylation and histone acetylation.

In our second major area of research, we have discovered that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is a potent antiapoptotic agent. We have characterized the effects and mechanism by which UDCA, as well as its taurine and glycine conjugates, functions to inhibit apoptosis. Specifically, we have used UDCA as a therapeutic agent to treat transgenic models of Huntington’s disease, as well as head trauma, acute stroke, spinal cord injury, Parkinson’s disease, myocardial infarction, retinitis pigmentosa and acute renal failure. The common characteristic shared by these disorders and many more human diseases is the role that apoptosis plays in disease progression. We have determined the common molecular mechanisms by which UDCA acts to preserve cell survival and cell function. UDCA is unique in that it is associated with no significant toxicity, crosses the blood-brain barrier and can be delivered orally or parenterally. My laboratory continues to study basic mechanisms and translational applications of UDCA. Of note, the FDA has recently approved its use in orphan drug status for the treatment of ALS.

Finally, my laboratory is actively characterizing the role of microRNAs in gene regulation for a number of different target organs and stem cell populations. In particular, we have identified specific microRNAs that may be involved in the progression of colon tissue from polyp to cancer; as well as identifying basic mechanisms involved in the uncoupling of protein and transcript in regenerating liver after partial hepatectomy. Our studies are both basic and translational in nature. We have recently begun studies to elucidate the role of genomic methylation in the control of microRNA biogenesis. These studies are particularly relevant to the onset and progression for a variety of different cancers. We are also identifying specific microRNAs as biomarkers for colon cancer that can be identified not only in tissue specimens, but also in blood. In collaboration with the Mayo Clinic, we have an ongoing project to identify the fundamental role that microRNAs play in colon cancer progression. Our future studies will focus primarily on basic mechanisms of microRNA function at the genomic and transcript levels, in addition to translational studies for both cancer and regeneration. Most notably, we have recently identified a small subset of microRNAs in mitochondria that may act as a rheostat for the control of apoptosis, cell proliferation and differentiation. In addition, we are also completing a study identifying a unique nuclear profile of microRNAs.

All of our research projects involve both basic and translational applications to human disease.

Recent Publications

• Kren BT, Yin W, Key NS, Hebbel RP, and Steer CJ: BOEC as a vehicle for transgene delivery of hepatocyte secreted proteins via Sleeping Beauty. Endothelium 14:97-104, 2007.
• Zhu J, Kren BT, Park CW, Bilgim R, Wong PY-P, and Steer CJ: Erythroid-specific expression of -globin by the Sleeping Beauty transposon for sickle cell disease. Biochemistry 46:6844-6858, 2007.
• Amaral JD, Castro RE, Solá S, Steer CJ, and Rodrigues CMP: p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem 282:34250-34259, 2007.
• Kren BT, Wong PY-P, Sarver A, Zhang X, Zeng Y, and Steer CJ: microRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biology 6:65-72, 2009.
• Kren BT, Unger GM, Sjeklocha L, Trossen AA, Korman V, Diethelm-Okita BM, Reding MT, and Steer CJ: Nanocapsule-delivered Sleeping Beauty mediates therapeutic FVIII expression in liver sinusoidal endothelial cells of hemophilia A mice. J Clin Invest 119:2086-2099, 2009.
• Kren BT, Wong PY-P, Shiota A, Zhang X, Zeng Y, and Steer CJ: Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 297:G1181-G1192, 2009.
• Sarver AL, French AJ, Borralho PM, Thayanithy V, Oberg AL, Silverstein KAT, Morlan BW, Riska SM, Boardman LA, Cunningham JM, Subramanian S, Wang L, Smyrk TC, Rodrigues CMP, Thibodeau SN, and Steer CJ: Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. BMC Cancer 9:401, 2009.
• Wang L, Tang H, Thayanithy V, Subramanian S, Oberg AL, Cunningham JM, Cerhan JR, Steer CJ, and Thibodeau SN: Gene networks and microRNAs implicated in aggressive prostate cancer. Cancer Res 69:9490-9497, 2009.
• Zhu J, Park CW, Sjeklocha L, Kren BT, and Steer CJ: High-level genomic integration, epigenetic changes, and expression of Sleeping Beauty transgene. Biochemistry 2010 Jan 22 [Epub ahead of print].
• Aravalli RN, Sahin MB, Cressman ENK, and Steer CJ: Establishment and characterization of a unique 1-µm diameter liver-derived progenitor cell line. Biochem Biophys Res Commun 391:56-62, 2010.
• Parry GJ, Rodrigues CMP, Aranha MM, Hilbert SJ, Davey C, Kelkar P, Low WC, and Steer CJ: Safety, tolerability and cerebrospinal fluid penetration of ursodeoxycholic acid in patients with amyotrophic lateral sclerosis. Clin Neuropharm 33:17-21, 2010.