Clifford Steer, M.D.

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 (click here to view CV in PDF) and has continued to be academically productive in his current area of research (Cliff Steer Research link).

Research

My laboratory is involved in two major areas of research.  The first involves a novel type of gene therapy that we have studied for the last eight years.  In contrast to traditional approaches, the technology involves the precise repair of genetic defects in cells using short fragments of DNA and/or RNA/DNA hybrid complexes.  While the exact mechanisms of nucleotide exchange are not entirely understood, our results from cell free assays and animal studies suggest that repair is achievable in both nuclear and mitochondrial DNA.  My laboratory has concentrated on the genetic correction of a number of different diseases, including hemophilia, sickle cell disease, Crigler-Najjar syndrome type I, ornithine transcarbamylase deficiency, b-thalassmeia, von Willebrand’s disease and several neurodegenerative diseases, including Huntington’s disease.  The technology of gene repair is exciting, somewhat controversial, and continually evolving.  The ability to correct a genetic sequence in combination with the information derived from the human genome project opens up a remarkable vista of potential therapeutic studies.  Unlike traditional gene therapy, gene repair corrects the precise genetic defect and allows the gene to be regulated endogenously without the potential toxicity of certain viral vectors.  It may provide the first cures to diseases such as sickle cell disease and hemophilia.  In parallel with the therapeutic applications, we continue to also study the basic mechanisms involved in gene conversion.  It is noteworthy that each of the approaches to DNA repair involves different, although overlapping pathways.

In addition to gene repair, we have also developed a more traditional type of gene therapy for diseases that are not amenable to genetic correction.  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 within 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, as well as a variety of adult stem cells.  Most recently, we have constructed a transposon system that utilizes RNA interference (RNAi) to inhibit translation of certain dominant negative proteins, including huntingtin and a1-antitrypsin.  We have already constructed the next generation of SB constructs that contain both inhibitor sequences (RNAi) and transgenes, thus providing long-term interference of the mutant proteins and expression of their wild-type sequences.  Finally, we have ongoing studies examining the effects of SB transposition on the methylation state of genomic DNA, as well as histone acetylation.  We are also studying the epigenetic changes associated with the use of micro and siRNAs, focusing primarily on methylation at the target gene and neighboring genomic regions.

In our second major area of research, we have discovered that ursodeoxycholic acid, an endogenous hydrophilic bile acid in humans, is a potent antiapoptotic agent.  Over the last several years we have characterized the effects and mechanism by which ursodeoxycholic acid, as well as its taurine and glycine conjugates, functions to inhibit apoptosis.  We have studied several animal models that are relatively accurate to their human counterparts.  Specifically, we have used ursodeoxycholic acid as a therapeutic agent to treat chemical and transgenic models of Huntington’s disease, as well as head trauma, acute stroke and cell transplantation for Parkinson’s disease.  The common characteristic shared by these disorders and many more human diseases is the role that apoptosis plays in disease progression.  In each case, we have determined that the bile acid is a markedly potent antiapoptotic agent that significantly improves the neurologic status in each of these disorders.  We have determined the common molecular mechanisms by which ursodeoxycholic acid acts to preserve cell survival and cell function.  In fact, ursodeoxycholic acid stabilizes the mitochondrial membrane and prevents apoptosis by inhibiting the permeability transition, mitochondrial membrane depolarization and channel formation, production of reactive oxygen species, release of cytochrome c, caspase activation, and cleavage of the nuclear enzyme poly(ADP-ribose) polymerase.  More recently, we have shown that ursodeoxycholic acid and its conjugates, inhibit the E2F-1/p53 apoptotic pathway and regulate NF-kB expression, thus modulating the expression of antiapoptotic Bcl-2 family members.  As a therapeutic agent, ursodeoxycholic acid is unique in that it is associated with no significant toxicity, crosses the blood-brain barrier and can be delivered intravenously, orally, or intrathecally.  There are, in fact, numerous conditions that could potentially benefit from its use including, acute myocardial infarction, autoimmune and ocular diseases, and a variety of neurodegenerative disorders.  Although my laboratory is involved primarily with basic and translational studies using animal models, we recently began a collaborative phase I/II clinical trial with Neurology on the use of ursodeoxycholic acid in ALS.

Recent Publications

Rodrigues CMP, Castro RE, and Steer CJ:  The role of bile acids in the modulation of apoptosis.  In E. Edward Bittar (Ed): The Liver in Biology and Disease: Principles of Medical Biology, Vol. 15, Elsevier Ltd., 2004, pp. 119-145.

Castro RE, Solá S, Ramalho RM, Steer CJ, and Rodrigues CMP:  The bile acid tauroursodeoxycholic acid modulates phosphorylation and translocation of Bad via phosphatidylinositol 3-kinase in glutamate-induced apoptosis of rat cortical neurons.  J Pharm Exp Ther 311:845-852, 2004.

Park CW, Chen Z, Kren BT, and Steer CJ:  Double-stranded siRNA targeted to the huntingtin gene does not induce DNA methylation.  Biochem Biophys Res Comm 323:275-280, 2004.

Rodrigues CMP and Steer CJ:  Tauroursodeoxycholic acid, a bile acid with in vivo antiapoptotic and neuroprotective properties.  In Paumgartner G, Keppler D, Leuschner U, and Stiehl A (Eds): Bile Acid Biology and its Therapeutic Implications, Falk Symposium 141, Springer, 2005, pp. 192-212.

Chen ZJ, Kren BT, Wong PY-P, Low WC, and Steer CJ:  Sleeping Beauty-mediated down-regulation of huntingtin expression by RNA interference.  Biochem Biophys Res Comm 329:646-652, 2005.

Castro RE, Solá S, Ma X, Ramalho RM, Kren BT, Steer CJ, and Rodrigues CMP:  A distinct microarray gene expression profile in primary rat hepatocytes incubated with ursodeoxycholic acid.  J Hepatology 42:897-906, 2005.

Yin W, Kren BT, and Steer CJ:  Site-specific base changes in the coding or promoter region of the human b- and g-globin genes by single-stranded oligonucleotides.  Biochem J 390:253-261, 2005.

Park CW, Kren BT, Largaespada DA, and Steer CJ:  DNA methylation of Sleeping Beauty with transposition into the mouse genome.  Genes Cells 10:763-776, 2005.

Solá S, Amaral JD, Castro RE, Ramalho RM, Borralho PM, Kren BT, Tanaka H, Steer CJ, and Rodrigues CMP:  Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-b1–induced apoptosis in rat hepatocytes.  Hepatology 42:925-934, 2005.

Fan GG and Steer CJ:  Cellular biology of the normal liver.  In Bacon BR, O'Grady JG, Di Bisceglie AM, and Lake JR (Eds):  Comprehensive Clinical Hepatology.  2^nd ed., Elsevier Limited, 2006, pp. 17-41.