Lymphangioleiomyomatosis, or LAM, is a rare lung disease that affects primarily women. In this disease cysts or abnormal air spaces replace the normal lung and progressively impair lung function. LAM can occur alone or as part of another disease called tuberous sclerosis (TS) that is characterized by tumors in different parts of the body such as the brain, skin, and kidneys. Importantly, both diseases share the same type of genetic error, which results in increased activity of a protein called mTOR that allows cells to have uncontrolled growth, as seen in tumors.

Lymphatic vessels play an important role in LAM. It is believed that LAM cells spread across the body through the lymphatic circulation. VEGF-D, a protein that increases lymphatic vasculature, is increased in LAM. Recently, this was linked to the impairment in lung function. However, we do not know which cell produces VEGF-D and what the mechanisms of production are.

In our project we will show that LAM cells have elevated levels of a protein called SYK. This increase in SYK leads to an increase in another protein called MCP-1. MCP-1 is important because it has been shown to be elevated in LAM lung and also MCP-1 attracts inflammatory cells. Inflammatory cells have been shown to produce large amounts of VEGF-D. We will also look at the effects of blocking syk in animal models of LAM to see if this leads to a decrease in tumors and lymphatics. Finally, in serum from patients with LAM we will measure syk and MCP-1 levels to see if they are good indicators of disease, when they are used alone or in combination with VEGF-D.

At the conclusion of this project, we hope to establish that SYK is a critical player in lymphangiogenesis in LAM. This is particularly important because there are drugs that inhibit SYK that are available and are currently in human clinical trials.