SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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