Ronald J. Koenig, M.D., Ph.D. Professor, Department of Internal Medicine Member, Cellular and Molecular Biology Program Director, Medical Scientist Training Program phone: 734-764-6176 (MSTP Office) fax: 734-764-8180 (MSTP Office) e-mail: rkoenig@umich.edu

Ronald J. Koenig is the Director of the University of Michigan MSTP. Dr. Koenig is a graduate of Yale University (B.S. in Molecular Biophysics and Biochemistry) and the Rockefeller University - Cornell University Medical College M.D./Ph.D. program. Following graduation from that program, Dr. Koenig did residency training in internal medicine and a fellowship in endocrinology at the Brigham and Women's Hospital, Boston MA. Dr. Koenig has been a faculty member at the University of Michigan since 1988 and Director of the MSTP since 1995. Dr. Koenig is active in basic research (see below), the clinical practice of endocrinology, and the teaching of medical and graduate students.

Dr. Koenig's current research is focused on regulation of gene expression by nuclear hormone receptors. The nuclear hormone receptors are part of a large family of zinc finger DNA binding proteins that alter transcription in a ligand dependent fashion. Dr. Koenig has been studying the receptors for thyroid hormone (TR) and retinoic acid (RAR), which are structurally and functionally closely related members of this gene family. These receptors often function as heterodimers with the retinoid X receptor (RXR), which is another member of the same gene family.

One area of current investigation concerns the role of RXR in TR regulation of gene expression. Questions being addressed include: is RXR required, does RXR serve to increase DNA binding of the TR, does RXR increase the transcriptional response in a step after DNA binding, does the role of RXR vary depending on the specific TR target gene, etc.

Another area of study involves the sick euthyroid syndrome. This syndrome is caused by virtually any serious medical or surgical illness, and is characterized by a low plasma T3 despite there being no intrinsic disease of the hypothalamic-pituitary-thyroid axis. An important aspect of this syndrome is the down-regulation of type 1 deiodinase, a liver enzyme that converts plasma thyroxine to T3. Dr. Koenig is investigating the molecular basis of this down-regulation, and has evidence that it is caused by cytokine-induced impairment of a co-activator protein called SRC-1. By understanding the molecular basis for the sick euthyroid syndrome, it should be possible to determine whether the syndrome should be treated, and if so, how.

The laboratory is collaborating with Dr. Kate Barald (Cell & Developmental Biology Dept.) to study the development of the inner ear. Bone morphogenetic protein 4 (BMP4) is essential for inner ear development. We have found that expression of BMP4 in the developing inner ear is driven by an unusual promoter in the gene's second intron, and that retinoic acid represses this promoter. Currently we are studying the mechanism of the retinoic acid effect and several other aspects of the function of the intron 2 promoter in development.

Representative Publications

Yu J, Koenig RJ. Regulation of hepatocyte thyroxine 5’ deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome. J. Biol. Chem. 275:38296-38301, 2000.

Wu Y, Xu B, Koenig RJ. Thyroid hormone response element sequence and the recruitment of retinoid X receptors for thyroid hormone responsiveness. J. Biol. Chem. 276: 3929-3936, 2001.

Thompson DL, Gerlach-Bank LM, Barald KF, Koenig RJ. Retinoic acid repression of BMP4 in inner ear development. Mol. Cell. Biol. 23:2277-2286 2003.