Dr. Andrew Scharenberg

My lab is interested in the molecular analysis of calcium entry mechanisms in the immune system.

Calcium is a critical regulatory second messenger for many types of gene activation events and for events which occur during cell division. The changes in cytosolic calcium which are involved in these types of events are often dependent on the entry of extracellular calcium. Furthermore, other divalent cations also play important roles in the proliferation and survival of non-excitable cells. Therefore, insight into the mechanisms which control the entry of calcium and other divalent cations into non-excitable cells will contribute significantly to our understanding of the mechanisms which regulate cell development and proliferation in both immunologic and non-immunologic contexts. However, to date, little is known about the molecular mechanisms which regulate the entry of calcium or other divalent cations into cells. My laboratory is focused on identifying and characterizing the biochemical mechanisms which regulate the entry of calcium and other divalent cations into immunologic cells and other types of non-excitable cells. I have four major ongoing areas of research:

I) Tec kinase-dependent signaling pathways:
A major interest of my laboratory is the characterization of the signaling pathways downstream from Tec kinase activation, one of whose major direct targets is phospholiphase C (an enzyme which causes the production of IP3 and diacylglycerol). In this area, we presently have an ongoing project currently focused on identifying the downstream targets of the DAG-activated kinases PKD and PKCnu.
2) ADP-ribose as a novel calcium entry second messenger
My laboratory has recently cloned and demonstrated the existence of an ADP-ribose gated ion channel which is expressed in many types of immune cells and other non-exciteable cells (Nature, 411:590-599). The existence of this channel suggests a novel role for ADPR as a calcium signaling second messenger, and the delineation and characterization of this pathway is presently the focus of a major project in the laboratory.
3) Characterization of a calcium channel required for cell viability
My lab also recently cloned the novel LTRPC7 channel and has shown that this channel is an MgATP-regulated ion channel required for cell viability (Nature, 411:590-95). This channel is unique in containing a kinase domain of presently unknown function, and is closely related to the putative melanoma metastasis suppressor gene Melastatin. The analysis of the role of this channel and Melastatin in eukaryotic cellular function is the focus of a major project in my laboratory.
4) Identification of novel regulatory pathways for calcium entry. My lab has cloned and characterized several other putative calcium channels expressed in immune and other non-exciteable cells, and has ongoing projects in several areas. Two of these projects are well along in development, such that I anticipate being able to submit NIH grants on one or more of them sometime in the next year.

I am actively interested in developing therapeutics targeted at ion channels expressed in non-exciteable cells. My laboratory and myself now have extensive experience in the expression and characterization of non-voltage activated ion channels, includinga library of cell lines either expressing various types of ion channels or lacking their expression. We have also developed or are developing assays suiteable for high throughput drug screening for each channel of interest.