Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in tuberous sclerosis complex 1 (TSC1) or TSC2. TSC is characterized by tumors in wide range of tissues, seizures, mental retardation, autism, and organ failure. Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease affecting 35% of women with TSC and is characterized by growth of abnormal and potentially metastatic atypical smooth muscle-like LAM cells within the lungs. Sporadic LAM can develop in women without TSC, owing to somatic mutations in TSC2 gene. It has been suggested that LAM cells undergo epithelial-mesenchymal transition (EMT). Src kinases are key regulators of cellular proliferation, motility, invasiveness and EMT. The central hypothesis of this proposal is that ?Src is activated in LAM cells and that increased Src activation contributes to down-regulation of E-cadherin and raises the oncogenic abilities of these cells. Thus, Src inhibition represents a potential therapeutic strategy to up-regulate E-cadherin in LAM cells, suppress EMT and reduce their oncogenic and metastatic potential.? The increased Src activity in TSC2-deficient cells is likely caused by inhibition of autophagy associated with hyper-activation of mTOR. Autophagy has been shown to be responsible for degradation of active Src. We propose to explore the use of Src inhibitors in LAM.

Public Health Relevance

Lymphangioleiomyomatosis (LAM) is a progressive destructive cystic lung disease. LAM cells grow and move faster than normal cells. We found that they have increased activity of a protein called Src. We are hoping that by inhibiting the activity of Src, we can reduce the growth and spread of LAM cells.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
1UH2TR000961-01
Application #
8599141
Study Section
Special Emphasis Panel (ZTR1-CI-2 (01))
Program Officer
Colvis, Christine
Project Start
2013-06-18
Project End
2014-05-31
Budget Start
2013-06-18
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,274,593
Indirect Cost
$340,789
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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