SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R C E L L B I O L O G Y P R O G R A M Dr. Zimmers’ current research focuses on the following questions: 1) Is dysregulation of the myostatin signaling pathway involved in the etiology of muscle wasting due to cancer, AIDS, congestive heart failure, burn, or sepsis in mouse models and in humans? 2) How does myostatin regulate muscle and fat mass in vivo? 3) What are the target genes induced by myostatin signaling? 4) How does myostatin influence glucose homeostasis? 5) How does myostatin-induced wasting differ from that induced by cytokines such as interleukin-6 (IL-6) or tumor necrosis factor (TNF)? Dr. Zimmers’ latest data derived from microarray analysis of RNA from muscle cells treated in vitro and in vivo with myostatin suggest that myostatin may regulate skeletal muscle mass on several levels, including by altering proteolysis, cell proliferation and apoptosis, and cell energetics/metabolism. Using this approach, she has identified a number of candidate genes that might control skeletal muscle regulation in normal development and disease. A second, long-standing focus of Dr. Zimmers’ research is the remarkable phenomenon of liver regeneration, a striking manifestation of tissue growth regulation. The laboratory has examined the roles of several members of the TGF-ß superfamily in liver regeneration using gene targeting, transgenesis and overexpression studies. Using such strategies, they demonstrated that the TGF-ß family members inhibin-ßC and –ßE, alone and in combination, and bone morphogenetic protein (BMP)-9 are not essential for liver regeneration after hepatectomy. Dr. Zimmers’ current work, done in collaboration with Leonidas G. Koniaris, M.D., focuses upon the role of the IL-6 signaling pathway in hepatocyte proliferation. They have shown that administering high levels of IL-6 to mice results in profound liver growth (with concomitant peripheral cachexia) without activating known growth factor signaling pathways. These results suggest that IL-6 may be a hepatocyte mitogen. Because elevated IL-6 levels also are associated with human liver disease, however, their current effort focuses upon identifying the mechanisms by which IL-6 induces liver growth and facilitate regeneration when administered acutely, but suppresses the regenerative response and potentially contributes to progressive liver injury and failure when present chronically. Finally, a chance observation that mice treated with high-dose IL-6 develop increased intestinal growth (increased gut length, diameter, and mass) has led to a third project examining the role of IL-6 in epithelial cell proliferation in the gut. Dr. Zimmers’ ultimate goal is to apply what is learned in the basic science laboratory to solving clinical problems, including the treatment of patients with muscle wasting disorders, obesity, diabetes, and liver disease. SELECTED PUBLICATIONS 2002 Zimmers, TA , Davies, MV, Koniaris, LG, Haynes, P, Tomkinson, KN, McPherron, AC, Wolfman, NM, and Lee, S-J. Cachexia induced by systemic myostatin administration in mice. Science 296:1486-1488, 2002. 2003 Sean, JJ, Klover, PJ, Nowak, IA, Zimmers, TA , Koniaris, LG, Furlanetto, RW, and Mooney, RA. Suppressor of cytokine signaling-3, a potential mediator of interleukin-6 dependent insulin resistance in hepatocytes. Journal of Biological Chemistry 278:13740-13746, 2003. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 101
T U M O R C E L L B I O L O G Y P R O G R A M Koniaris, LG, McKillop, IH, Schwartz, SI, and Zimmers, TA . Liver regeneration. Journal of the American College of Surgeons 197:634-59, 2003. Zimmers, TA , McKillop, IH, Pierce, RH, Yoo, JY, and Koniaris, LG. Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology 38:326-34, 2003. Klover, PJ, Zimmers, TA , Koniaris, LG, and Mooney, RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784-89, 2003. HIGHLIGHTS/DISCOVERIES • Demonstrated that overexpression of the TGFß family member, myostatin, leads to hypoglycemia and muscle and fat wasting despite adequate food intake, suggesting a role for the myostatin pathway in the etiology or treatment of human wasting diseases such as cancer cachexia. • Observed that overexpression of the inflammatory cytokine IL-6 leads to hypoglycemia and peripheral cachexia, along with increased liver and bowel growth, suggesting a role for IL-6 in human wasting syndromes and in treatment or progression of liver disease, hepatocellular carcinomas, or short gut syndrome. 102 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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G L O S S A R Y IFN—interferon IL
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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