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Teresa A. Zimmers, PhD

Associate Professor of Research, Department of Surgery

Faculty Biography

The overall aim of my research is to understand the molecular mechanisms regulating organ size. The model system and application we have chosen to study is regulation of skeletal muscle mass in disease. Muscle size is highly plastic and extraordinarily responsive to changes in single genes or pathways. Furthermore, skeletal muscle protein stores and metabolic functions play important and essential roles in the physiologic response to injury and disease. We seek to discover the molecular pathways regulating muscle plasticity in the setting of serious illness. The long term goal is to develop targeted interventions for muscle preservation and functional recovery in chronic disease.

 

Current Research Projects

  • IL-6 family ligands and STAT3 signaling in muscle wasting of cancer and burn
  • Sonic Hedgehog, Smoothened, and GLI1 in muscle wasting of cancer cachexia and inflammation
  • Myostatin family ligands and ACVR/SMAD signaling in cancer and burn cachexia
  • Molecular phenotyping of cancer cachexia
  • The role of protein redistribution in the pathobiology of injury and muscle wasting

 

Grant Support

Lustgarten Foundation                                                                                                                  12/13-12/31/17

Role: Principal Investigator

Phenotyping Pancreatic Cancer Cachexia: a Bridge to personalized medicine

Cachexia afflicts some 80% of all patients with pancreatic cancer. Cachexia itself is estimated to kill 1/3 of all cancer patients. Despite its impact, little is known about cachexia in general and in pancreatic cancer in particular. Indeed, fewer than 140 original publications exist on pancreatic cancer cachexia and of those, fewer than 10 address molecular mechanism. Three microarray datasets are available, one in fat and two in muscle, representing 43 cancer patients, only a fraction of whom had pancreatic cancer. There is a dire need for clinical data in order to translate findings in model systems to treatments in patients. In the course of my laboratory’s investigations into the mechanistic basis of cachexia, we have identified distinct cachexia phenotypes within and across diverse disease models in mice. Moreover, different molecular drivers of cachexia also produce distinct systemic phenotypes and gene expression profiles, although all produce muscle wasting and weight loss. We suspect that the molecular drivers of cachexia in pancreatic cancer are possibly as numerous and diverse as the tumor promoters/suppressors that give rise to cancer. If so, the piecemeal study of pancreatic cancer cachexia to date has been woefully inadequate. Here we propose to leverage my lab’s expertise in cachexia signaling, transcriptional regulation and mouse models of systemic disease against Indiana University’s outstanding and busy pancreatic cancer surgical program and state-of-the art genomics group in order to perform molecular phenotyping of pancreatic cancer cachexia. Clinical data on body composition, co-morbidities, laboratory values and tumor characteristics will be culled from diagnostic CT scans and hospital records. BMI, weight loss history, fatigue measures and functional status will be determined at interview. Serum, muscle, fat and tumor samples will be collected at surgery. Serum cytokines, myostatin activity, and in vitro muscle and fat wasting activity will be quantified and compared with protein signaling and gene expression profiles of fat and muscle tissue. Tumors will be orthotopically implanted in mice. Data will be analyzed for hypothesis testing on known/suspected drivers, molecular signatures of cachexia will be sought, and the entire dataset will be made publicly available for other investigators to query. Ultimately we will generate a unique, essential resource for propelling therapeutic interventions

 

NIH R01 CA122596-04A1                                                                                                       07/02/10-04/30/15

Role: Principal Investigator

Manipulation of STAT3 Signaling for Muscle Preservation in Cancer Cachexia

In cancer patients, cachexia and mortality correlate closely with elevated serum IL-6 levels and acute phase response proteins.  In mice, IL-6 administration causes systemic wasting and IL-6 inhibition ameliorates cancer cachexia. However, the molecular mechanisms linking IL-6 and skeletal muscle wasting are unknown. Our hypothesis is that IL-6 signaling in mature myofibers activates STAT3 and STAT3 target genes that together result in increased proteolysis and reduced hypertrophy. The net result is myofiber wasting. The studies in this new NCI R01 application will determine definitively the role of the IL-6/gp130/STAT3 signaling pathway in muscle growth regulation in mature myofibers in normal physiology and in cancer cachexia.

 

  • NIH R01 GM09275-04A1                                                                                                        08/01/10-05/31/15

Role: Principal Investigator

Myostatin Family Signaling in Burn-Injury Related Muscle Wasting

Myostatin is a skeletal muscle-specific member of the Transforming Growth Factor-β superfamily and a potent, tonic muscle growth inhibitor. The objective of this application is to determine the mechanisms by which myostatin modulates muscle mass after burn injury. Our hypothesis is that myostatin and related ligands promote muscle wasting after burn injury, and that altering myostatin family signaling after burn will change burn survival, muscle mass and function. Data from our mouse burn model indicate that in the acute post-burn period, myostatin activity and muscle wasting may facilitate survival. In the longer term, myostatin-mediated muscle wasting becomes maladaptive, reducing function and increasing vulnerability.

 

  • PA CURE

Role: Principal Investigator

Involvement of Hedgehog Signaling in Muscle Wasting of Cancer Cachexia

Sonic hedgehog promotes muscle development in embyrogenesis through proliferation of muscle precursor cells and facilitates repair of skeletal muscle in adults though effects on skeletal muscle stem cells known as satellite cells. Whether sonic hedgehog also plays a role in committed, mature skeletal muscle fibers is unknown. Cytokines are elevated in cachexia and can induce muscle wasting either directly or indirectly. TNF and other cytokines can induce expression of sonic hedgehog in pancreas and other tissues. Our hypothesis is that inflammatory cytokines in cancer induce expression of sonic hedgehog and activation of its signaling pathway in skeletal muscle, leading to muscle wasting. Inhibition of hedgehog signaling will preserve muscle and promote functionality and survival in cancer.

 

  • 2012F-RFA67-16                                                                                                                      

Commonwealth of Pennsylvania Health Research Formula Fund

Role: Principal Investigator

Development and Phenotyping of New Mouse Models of Cancer Cachexia

We developed over a dozen new models of cachexia due to pancreatic, ovarian or colon cancer. We are characterizing the plasma cytokine profiles and muscle gene expression profiles of these models to shed light on the progression of muscle wasting in cancer.

 

  • NIH R01 DK096167-01 PI Koniaris

Role: Co-Investigator (20%)

EGFR therapies for fatty liver surgery

As obesity and overweight increase among Americans, so does the incidence of fatty liver. Even the mildest forms of fatty liver predispose patients to liver failure after liver resection, thereby limiting the application of partial hepatectomy for treatment of liver metastases and the use of fatty liver in transplantation. We found a primary defect in fatty liver is loss of EGFR expression. Restoration of EGFR by gene therapy or with resveratrol restores normal regeneration. In this project we are examining the signaling pathways necessary for regeneration and the mechanism of resveratrol rescue using both mice and Ossabaw mini-pigs.

 

Future Plans

The number of circulating ligands currently known to cause cachexia is small. We have identified four new cytokines with muscle-wasting activity. We will pursue functional characterization of those new ligands and their signaling pathways using genetic and pharmacological approaches. One quarter of our effort is invested in probing new secreted factors, transcription modulators and investigational approaches to promote discovery of novel targets for muscle growth regulation. To broaden the impact of our work, we are seeking collaborations among faculty from a broad variety of disciplines in a Cachexia Working Group in the Simon Cancer Center and the Department of Surgery.

 

Selected Publications

Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, Koniaris LG and TA Zimmers. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Phys Endo Metab, 303(3):E410-21.

Pedroso FE, Spalding PB, Cheung MC, Yang R, Gutierrez JC, Bonetto A, Zhan R, Chan HL, Namias N, Koniaris LG, TA Zimmers. Inflammation, organomegaly and muscle wasting despite hyperphagia and polydipsia in a standardized mouse model of burn injury-induced cachexia. Journal of Cachexia, Sarcopenia Muscle, Epub ahead of print, 2012 Mar 29.

Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG, TA Zimmers. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS ONE 6(7): e22538. doi:10.1371/journal.pone.0022538. Epub 2011 Jul 20.

Yang R, Cheung MC, Pedroso FE, Byrne MM, Koniaris LG and TA Zimmers. Obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. J Surg Research, 170(1):e75-83. Epub 2011 Jul 20. PMID: 21704331

Benny Klimek ME, T Aydogdu, MJ Link, M Pons, LG Koniaris, and TA Zimmers. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochemical Biophysical Research Communications, 391(3): p. 1548-54, Epub 2009/12/29, 2010.

Cheung MC, PB Spalding, JC Gutierrez, W Balkan, N Namias, LG Koniaris, and T.A. Zimmers. Body surface area prediction in normal, hypermuscular, and obese mice. J Surgical Research, 153(2): p. 326-31, Epub 2008/10/28, 2009.

Koniaris LG, KW Goodman, J Sugarman, U Ozomaro, J Sheldon, and TA Zimmers. Ethical implications of modifying lethal injection protocols. PLoS Medicine, 5(6): p. 0845-0849, Epub 2008/06/13, 2008.

 Housri N, MC Cheung, LG Koniaris, and TA Zimmers. Scientific impact of women in academic surgery. J Surgical Research, 148(1): p. 13-6, Epub 2008/06/24, 2008.

 Zimmers TA, J Sheldon, DA Lubarsky, F Lopez-Munoz, L Waterman, R Weisman, and LG Koniaris. Lethal injection for execution: chemical asphyxiation? PLoS Medicine, 4(4): p. 0646-0653, Epub 2007/04/26, 2007.

Koniaris LG, *TA Zimmers, DA Lubarsky, and JP Sheldon. Inadequate anaesthesia in lethal injection for execution. Lancet, 365(9468): p. 1412-4, Epub 2005/04/20, 2005.

Zimmers TA, IH McKillop, RH Pierce, JY Yoo, and LG Koniaris. Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology, 38(2): p. 326-34, Epub 2003/07/29, 2003.

Zimmers TA, MV Davies, LG Koniaris, P Haynes, AF Esquela, KN Tomkinson, AC McPherron, NM Wolfman, and SJ Lee. Induction of cachexia in mice by systemically administered myostatin. Science, 296(5572): p. 1486-8, Epub 2002/05/25, 2002.

 

Department of Surgery | 545 Barnhill Drive, Emerson Hall 203, Indianapolis, In 46202 | Phone: (317) 274-5771