Research Interests

The lipid sphingosine-1-phosphate (S1P) is indispensable for embryonic vascular development and for lymphocyte circulation. Mice that cannot make S1P die of hemorrhage at mid-gestation. Mice in which the S1P-generating enzymes are conditionally deleted in adulthood are immune-compromised, as T and B cells cannot exit lymphoid organs and thus cannot travel to sites of infection. S1P has also been implicated in angiogenesis and inflammation. Drugs that target S1P receptors have been proposed as anti-angiogenic cancer therapies, and are in clinical trials as immune suppressants. Despite the critical roles of this signaling lipid in mammalian biology, we understand little about how its production and distribution are regulated. We will investigate these control mechanisms, and we will use in vivo models to explore how S1P distribution affects blood vessel development and the immune system.

The first question we will address is how S1P is confined to circulatory fluids. Plasma S1P is at micromolar concentrations, and lymph S1P is in the 100 nanomolar range. Despite the fact that lymph is essentially transudated plasma, and despite the fact that that the carriers of S1P (albumin and high density lipoproteins) transit from plasma to lymph, S1P itself is destroyed as it leaves the blood and must be resupplied to the lymph.

We will ask what cell types and enzymes are responsible for keeping S1P levels low in the tissues. Our second aim will be to test the hypothesis that S1P serves as a marker of circulatory fluids, and that its presence in tissues signals vessel damage. Vascular endothelial cells and innate immune cells can respond to S1P, and S1P clearance may be important to prevent inappropriate angiogenesis and to prevent a chronic inflammatory response by tissue-resident cells. Additional questions we plan to address include how S1P, a polar lipid, is transported across the cell membrane, and what is the function of the S1P receptor S1P4, which is highly expressed in the immune system.