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.
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.
|Guan, Wei-Jie; Huang, Yan; Chen, Chun-Lan et al. (2018) Sputum purulence-associated microbial community compositions in adults with bronchiectasis. J Thorac Dis 10:5508-5514|
|Guan, Wei-Jie; Yuan, Jing-Jing; Li, Hui-Min et al. (2018) Altered community compositions of Proteobacteria in adults with bronchiectasis. Int J Chron Obstruct Pulmon Dis 13:2173-2182|
|Guan, Wei-Jie; Gao, Yong-Hua; Xu, Gang et al. (2016) Bronchodilator response in adults with bronchiectasis: correlation with clinical parameters and prognostic implications. J Thorac Dis 8:14-23|
|Zhu, Zheng; Xie, Yanqing; Guan, Weijie et al. (2016) Leukotriene D4 nasal provocation test: Rationale, methodology and diagnostic value. Exp Ther Med 12:525-529|
|Zhu, Zheng; Xie, Yanqing; Guan, Weijie et al. (2016) Correlations of nasal responses to leukotriene D4 and histamine nasal provocation with quality of life in allergic rhinitis. Asia Pac Allergy 6:245-252|
|Guan, Wei-Jie; Yuan, Jing-Jing; Gao, Yong-Hua et al. (2016) Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis. Sci Rep 6:28467|
|Zhu, Zheng; Xie, Yanqing; Guan, Weijie et al. (2016) FeNO for detecting lower airway involvement in patients with allergic rhinitis. Exp Ther Med 12:2336-2340|
|Tyryshkin, Alexey; Bhattacharya, Abhisek; Eissa, N Tony (2014) SRC kinase is a novel therapeutic target in lymphangioleiomyomatosis. Cancer Res 74:1996-2005|