Scientific Objective and Rationale: Kidney angiomyolipomas are a common kidney tumor in children and adults affected with tuberous sclerosis complex (TSC), being seen in up of 80% of those of age >12. Angiomyolipomas are closely related to lymphangioleiomyomatosis (LAM), a common lung disorder in adult TSC women. We have learned a great deal about both the molecular basis and clinical aspects of renal angiomyolipomas and LAM. However, the cell of origin and the role of driver events beyond genetic alterations in TSC2 and TSC1 in angiomyolipoma and LAM development are unknown. In recent studies, we have shown that angiomyolipomas and LAM tumors have a unique pattern of gene expression, different from all known cancers and normal tissues. How gene expression is regulated in different cancer types is a fundamental question in cancer research. Why do certain tumors develop in TSC, which are not seen in other tumor syndromes? And why do other cancer types not occur at markedly elevated rates in TSC individuals? Epigenetics is the study of the organization of the genome, and how it affects gene expression. Nothing is known regarding the epigenetic changes in TSC tumors. We hypothesize that it is the chromatin state of the cell in which second hit loss of TSC2 (or TSC1) occurs that determines whether that cell has indefinite growth potential and leads to, e.g., angiomyolipoma tumor, or rather undergoes senescence. Here, we propose to study the organization of the genome and how epigenetic marks influence gene transcription in angiomyolipoma and LAM in TSC patients.

Principal Investigator's Career Goals: I am highly motivated and dedicated to perform innovative research focused on understanding how TSC tumors develop in order to decrease its clinical impact. My ultimate goal is to become an independent researcher in TSC and strive for excellence in all three areas of academe: research, service, and teaching. I am very interested to develop a scientific career in the United States, though returning to my home country is also attractive in order to serve the Greek people. Professor Kwiatkowski's lab has a 25-year track record of cutting-edge genetic studies in TSC, dating back to their discovery of the TSC1 gene, and including recent innovative methods for findings mutations in TSC patients. The opportunities for innovative research in his laboratory and the contact with other senior researchers are invaluable for accomplishing my goals for a successful leading career at the forefront of TSC research. I have been with Dr. Kwiatkowski since September 2015 and have worked on multiple TSC projects since then. I have been trained in next-generation sequencing technologies and interpretation of that data. I work regularly with well-known experts from the Broad Institute, Dana-Farber Cancer Institute, and Harvard Medical School, and I attend multiple cancer programs and meetings, interacting with leading scientists in the TSC and cancer field.

Clinical Applicability and Impact of the Research, Contributions to Advancing the Field: The clinical application of this research will be the following. First, our results should elucidate the cell of origin of angiomyolipoma and LAM tumors occurring in TSC patients. Second, our results will enable the identification of genes whose expression is critical for development of these tumors beyond TSC2/TSC1 and mTOR. Third, by critically assessing the importance of gene expression in angiomyolipoma/LAM, we will discover completely novel, currently unknown, therapeutic strategies for these conditions. Using cell lines and mouse models to validate our findings, we expect that our work will enable efficient therapies for angiomyolipoma and LAM.