Sarcomas primarily affect children and young adults. For pediatric oncologists, sarcomas are a major problem. Most are extremely aggressive and current protocols of surgery, radiation and chemotherapy are not adequate. Significant improvement for many sarcomas will require a detailed understanding of the genetic factors responsible for its progression, so that a gene targeted-based therapy can be developed to manage the cancer. Each sarcoma is likely to require its own specific molecular-based therapies for its management. To achieve these goals the information based for each sarcoma will likely require generating a mouse model of the human cancer that accurately simulates the human condition. The criterion to establish a "good" mouse model for the human cancer is now very rigorous. Each human cancer is being classified with a genetic fingerprint involving the expression profile of thousands of genes. Having established authenticity of the mouse model, it can be used to identify the secondary genetic events responsible for its progression. Having in turn identified the genetic players, their identity can be used as a platform to generate a rational approach to therapeutic development. We have successfully modeled alveolar rhabdomyosarcoma and synovial sarcoma and are in the process of modeling Ewing's sarcoma. We will use these mouse models to determine the secondary genetic events responsible for their progression. We also propose to generate improved third generation mouse models that will initiate the cancers by inducing the appropriate chromosomal translocation in their cell of origin. The therapeutic potential of iPS cells for cell-base therapy of many major human diseases is enormous. However, attaining this potential will require a much deeper understanding of adult stem cell biology, which is nature's normal means for maintaining tissue homeostasis and response to modest trauma. We propose to continue our functional studies of two adult stem cell systems, intestinal stem cells and neuronal stem cells. These two stem cell systems are at opposite ends of the spectrum in terms of the frequency of tissue turnover that they maintain. By comparing these two systems we may gain insights into how adult stem cell systems can be modulated to alter their output.

Public Health Relevance

The grant proposal is directed at two goals: 1) modeling human sarcomas in the mouse and, 2) studying intestinal and neuronal stem cells. The first goal is directed at determining the genetic events responsible for progression of synovial and Ewing's sarcoma. Through the second goal we hope to gain a better appreciation of how adult stem cells are used to maintain tissue homeostasis and respond to modest trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM021168-39
Application #
8513334
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
1976-12-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
39
Fiscal Year
2013
Total Cost
$409,790
Indirect Cost
$134,763
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Jones, K B; Su, L; Jin, H et al. (2013) SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene 32:2365-71, 2375.e1-5
Su, Le; Sampaio, Arthur V; Jones, Kevin B et al. (2012) Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 21:333-47
Yan, Kelley S; Chia, Luis A; Li, Xingnan et al. (2012) The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci U S A 109:466-71
Makki, Nadja; Capecchi, Mario R (2012) Cardiovascular defects in a mouse model of HOXA1 syndrome. Hum Mol Genet 21:26-31
Makki, Nadja; Capecchi, Mario R (2011) Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development. Dev Biol 357:295-304
Guo, Ting; Mandai, Kenji; Condie, Brian G et al. (2011) An evolving NGF-Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates. Nat Neurosci 14:31-6
Fu, Yuhong; Tvrdik, Petr; Makki, Nadja et al. (2011) Precerebellar cell groups in the hindbrain of the mouse defined by retrograde tracing and correlated with cumulative Wnt1-cre genetic labeling. Cerebellum 10:570-84
Chen, Shau-Kwaun; Tvrdik, Petr; Peden, Erik et al. (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775-85
Haldar, Malay; Hedberg, Matthew L; Hockin, Matthew F et al. (2009) A CreER-based random induction strategy for modeling translocation-associated sarcomas in mice. Cancer Res 69:3657-64
Haldar, Malay; Karan, Goutam; Tvrdik, Petr et al. (2008) Two cell lineages, myf5 and myf5-independent, participate in mouse skeletal myogenesis. Dev Cell 14:437-45

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