Heller Brown Lab

 

Research

Joan Heller Brown, PhD

Professor & Chair

 

GPCRs in growth regulation

The brain contains a population of cells called astrocytes which serve to support neurons. Unlike neurons, astrocytes proliferate in response to brain injury and also express genes that mediate inflammation and cell growth. Aberrant astrocyte growth can lead to development of scar tissue, to inflammation, or to glioblastoma, a particularly aggressive form of cancer.  We are examining novel mechanisms by which inflammatory mediators that act on G-protein coupled receptors (GPCRs) stimulate astrocyte proliferation and gene expression.


Thrombin, S1P and LPA are mediators of inflammation and potent activators of glial cell growth. We believe this occurs because these receptors couple to the oncogenic G-protein G12/13 which leads to activation of the small G-protein RhoA. We are studying two intriguing novel targets of RhoA.  One is phospholipase C epsilon, unique in that it appears to localize to an intracellular compartment and to act as guanine nucleotide exchange factor for another small G-protein Rap1 which activates the oncogene BRaf. 


A second signal transducer of considerable interest is Cyr61/CCN1 which is highly induced in glioblastoma, required for their proliferation, and acts as a secreted extracellular matrix protein that engages integrins, providing a cooperative mechanism for sustained mitogenic responses to GPCR stimulation.


We carry out molecular analysis on glioblastoma cell lines, using siRNA or lentiviral shRNA expression to knock down molecules of interest, as well as primary astrocytes isolated from brains of wild type and knockout mice. We assess changes in cell signaling events by Western blotting, by FRET based fluorescence imaging of second messengers and kinases, and by cell proliferation and apoptosis assays. For in vivo studies we examine the role of PLC epsilon and Cyr61 on growth of tumor cells and on tissue response to brain or spinal injury in mice.