The objective of this proposal is to investigate the signaling pathways that give rise to tumors in tuberous sclerosis complex (TSC). Approximately 50,000 Americans and more than a million people worldwide suffer from TSC, an autosomal dominant syndrome that affects multiple organ systems. Afflicted individuals suffer complications such as seizures, renal hemorrhage, and respiratory failure as a result of abnormal growths in the brain, kidneys and lung, among others. Treatment is palliative and no effective cure is known. Genetic research has identified two genes that are responsible for TSC, and recent studies have revealed their role in regulating two signaling pathways: the mTOR and beta-catenin signaling. However, there is a paucity of evidence to link the mTOR pathway to tumor development and abnormal beta-catenin activity to TSC pathology in vivo. The central hypothesis is that aberrant activity of both pathways leads to tumorigenesis. Using a combination of cellular, genetic and pharmacologic approaches, we propose to analyze the relative contribution of each of these two pathways in the pathogenesis of TSC-related tumors.
The specific aims are 1) to assess the components of the mTOR and beta-catenin pathways in modulating tumorigenicity of Tsc2-1- cells, 2) to investigate genetic interaction between Tsc2 and components of the two pathways, and 3) to elucidate the role of mTOR during tumor initiation. Together, results of these experiments will provide a better appreciation of the in vivo relevance of these two signaling cascades in TSC biology. Our long-term goal is to exploit the mechanisms of these pathways in the development of clinical therapy for TSC-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102662-02
Application #
6891463
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Snyderwine, Elizabeth G
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$310,780
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kenerson, Heidi L; Subramanian, Savitha; McIntyre, Rebecca et al. (2015) Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt. PLoS One 10:e0117000
Kenerson, Heidi L; Yeh, Matthew M; Yeung, Raymond S (2011) Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation. PLoS One 6:e18075
Barnes, Elizabeth A; Kenerson, Heidi L; Mak, Baldwin C et al. (2010) The loss of tuberin promotes cell invasion through the ß-catenin pathway. Am J Respir Cell Mol Biol 43:617-27
Jiang, Xiuyun; Kenerson, Heidi; Aicher, Lauri et al. (2008) The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. Am J Pathol 172:1748-56
Kenerson, Heidi; Folpe, Andrew L; Takayama, Thomas K et al. (2007) Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol 38:1361-71
Carroll, Patrick A; Kenerson, Heidi L; Yeung, Raymond S et al. (2006) Latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol 80:10802-12
Mak, Baldwin C; Kenerson, Heidi L; Aicher, Lauri D et al. (2005) Aberrant beta-catenin signaling in tuberous sclerosis. Am J Pathol 167:107-16
Kenerson, Heidi; Dundon, Trevor A; Yeung, Raymond S (2005) Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res 57:67-75
Yeung, Raymond S (2004) Lessons from the Eker rat model: from cage to bedside. Curr Mol Med 4:799-806