Grant: CIHR Fellowship

Lymphangioleiomyomatosis (LAM) is a rare devastating lung disease that predominantly affects young women and results in proliferation of lung smooth muscle, growth throughout the lungs leading to obstruction and respiratory failure. There are two forms of LAM: Sporadic LAM for which the genetic basis is unknown and TSC-LAM in women who have the familial disease tuberous sclerosis complex (mutations in the TSC1 or TSC2 genes). TSC1/2 are well-characterized tumour suppressor genes that contain a GTPase activating protein (GAP) and that loss of TSC1/2 leads to hyper-activation of the mammalian target of rapamycin (mTOR), a multi-subunit kinase that regulates cell growth, invasion, metabolism and resistance to apoptosis. Lung transplants are often the only treatment option for late stage LAM patients with a 5 year survival rate of only 65%. The lack primary cell lines or appropriate disease specific model organisms often limits LAM research. Recent advances in induced pluripotent stem cells (iPS) in which human fibroblasts are reprogrammed to pluripotent stem cells using a genetic defined set of factors (KLF4, SOX2 and OCT4) show promise in allowing for the generations of patient specific disease models such as LAM. Our Hypothesis is that generation of iPS cells from fibroblast patients of TSC-LAM and normal control wildtype iPS cells can be differentiated to smooth muscle lung cells and serve as a model to identify novel drug targets and epigenetic alterations. In this proposal we aim to generate and validate human primary cell culture models and mouse xenograft models that can recapitulate LAM. Using these validated models we will explore LAM for epigenetic alterations and use these models as pre-clinical models to identify new therapeutic agents that are effective against LAM and not normal control tissue. Deciphering the methylome and using drug discovery will allow for novel insights and treatment options in to LAM.