Tuberous sclerosis complex (TSC) is a multi-organ genetic disorder with an estimated incidence of one in 6,000 live births. About 30% of women with TSC have lymphangioleiomyomatosis (LAM), a progressive lung disease characterized by abnormal proliferation of smooth muscle-like cells throughout the lungs, leading to lung destruction and eventual respiratory failure. The cause of the tumor development in various tissues is not well understood. A recent White Paper for the TSC Alliance found that understanding the molecular mechanisms of TSC and LAM, developing new biomarkers to follow disease and treatment progression and drug screening are critical. The generation of patient-derived cell culture models of TSC will advance all of these goals. A 2007 breakthrough technology, honored by the 2012 Nobel Prize, is that human adult cells can be reprogrammed into stem cells known as induced pluripotent stem cells (iPSCs). iPSCs are capable of becoming any cell type in the body. We propose to generate iPSCs from tumor cells and normal cells of individuals with TSC and use these cells to model TSC and LAM in tissue culture dishes as well as in mice. By comparing the characteristics of tumor cell-derived iPSCs with those of normal TSC-patient derived iPSCs and non-TSC patient iPSCs, the cause of TSC and LAM will be better understood, which is the first step to identify novel disease biomarkers and new drugs to treat TSC and LAM. |
