Investigating the tissue origin of LAM
Lymphangioleiomyomatosis (LAM) is a rare, chronic disease almost exclusively affecting females. LAM results from the growth and accumulation of abnormal cells in the lung, which ultimately leads to severe lung destruction. Lung transplantation is currently the only therapeutic option for advanced LAM disease. Although LAM is thought to originate from outside the lung, the specific tissue of origin is unknown. We compared LAM gene expression patterns to a comprehensive collection of 369 other tissue types representing normal or diseased states of virtually all tissues of the body. This analysis demonstrated that LAM is closely related to normal and cancerous tissues of the uterus. We propose to directly test the possible uterine origin of LAM by further examining whether additional LAM lesions exhibit gene expression patterns and functional properties of uterine tissues. We will also work to model the disease in mice by inducing a LAM-specific mutation directly within the uterus. By conducting a comprehensive set of experiments from determination of the cellular origins of the disease to testing the hypothesis in animals, we will be able to understand what is causing the disease. Our proposed studies will not only clarify the origins of LAM, but will aid in the development of novel therapeutic avenues for this orphan disease.