My laboratory is focused on two tumor suppressor gene diseases associated with renal tumorigenesis and hamartomas: tuberous sclerosis complex (TSC) and Birt-Hogg-Dube (BHD) syndrome. I have a particular interest in lymphangioleiomyomatosis (LAM), which is the pulmonary manifestation of TSC. My group is perhaps best known for discovering that LAM is caused by somatic TSC2 mutations, and that LAM cells metastasize despite the fact that they are histologically benign, leading to the now widely accepted "benign metastasis" model. Remarkably, LAM affects almost exclusively young women. The mechanisms underlying this female predominance are a major focus of my laboratory.

In addition to studying human tumor specimens from patients with these diseases, we use cultured cells, mice, and Schizosaccharomyces pombe as models. Our work has led to basic discoveries related to regulation of the mTOR signaling pathway by the cell cycle and by estrogen and regulation of amino acid homeostasis by the TSC and BHD homologs in yeast. We were the first to demonstrate that the protein products of the TSC1 and TSC2 genes (hamartin and tuberin, respectively) physically interact and reported the the first post-translational modification of the TSC1 protein (CDK1 phosphorylation). We generated the first yeast model of BHD and the first heterozygous mouse model of BHD. BHD and TSC have distinct clinical similarities, including facial hamartomas, chromophobe renal cell carcinomas, and spontaneous pneumothorax (lung collapse). Given these similarities, our work in S. Pombe has yielded surprising results: the TSC and BHD protein homologs have opposing roles in the regulation of amino acid homeostasis, including regulation of amino acid permeases and intracellular amino acid levels. We remain intensely interested in the function of the BHD protein, using cell culture and mouse models in addition to our yeast model. My research program is by its nature interdisciplinary, bringing together different areas of medicine and biology. The mechanisms we study have relevance to cell biology, genetics, pathology, and developmental biology, and the models we study include humans, mice, and yeast.