Lymphangioleiomyomatosis (LAM) is a rare lung disease limited principally to women of child bearing age and is characterized by an abnormal proliferation of smooth muscle cells in the pulmonary interstitium. The only viable treatment for the disease is lung transplantation. The limited available information on LAM demonstrates correlations with 2 metabolic phenomena, one being fluctuations in the female sex steroid hormone estrogen and the other being the genetic disease tuberous sclerosis. Recent work in our laboratory, and preliminary data presented in this proposal, for the first time offer a direct link between the activities of the gene mapping to the genetic locus for tuberous sclerosis (TSC2) with transcription events mediated by estrogen activation of its intracellular receptor (ER) and the intracellular signaling switch calmodulin (CaM). Our current working hypothesis is that LAM is an aberration in intracellular signaling that leads to inappropriate gene regulation of specific cell cycle control components. To establish the potential biological relevance of this hypothesis to the pathogenesis of LAM, the following specific aims will attempt to dissect the relationships between TSC, CaM and in the ER modulation of transcription and cell proliferation events. 1) Characterization of CaM-specific regulatory sequences in the TSC2 gene. 2) Characterization of Ca++/CaM signaling in TSC2/ER-mediated events. 3) Characterization of the role of calcium regulated phosphorylation events might play in TSC2-modulated steroid receptor-mediated transcription. 4) Characterization of TSC1?s role in the TSC2/calmodulin signaling pathway. 5) Characterization of links between TSC/CaM signaling and cell cycle control. The preliminary data presented in this grant provide a strong foundation for dissecting the molecular events associated with normal function of the TSC2 genes. The intriguing link among TSC2, ER and CaM for the first time offers a potential mechanism for cell proliferation events as observed with the loss of heterozygosity or deletion of the TSC genes. With this knowledge also comes potential avenues for drug development and interventions into this heretofore vaguely understood disease condition. It is truly believed that the results of these studies will provide critical insight into the pathology of LAM (and most likely tuberous sclerosis) as well as avenues for intervention into that pathology.
