EXCEED THE SPACE PROVIDED. The endothelial barrier of the brain is characterized by specialized endothelial cells with low paracellular permeability. Along with the basement membrane and other cell types, the blood brain barrier (BBB) is an important regulator of normal brain metabolism. Brain tumors disrupt the integrity of the BBB, and in malignant glioblastoma multiforme (GBM), compromise of the BBB is associated with increased GBM tumor growth. Our previous studies have demonstrated that Src is essential for the maintenance of endothelial barrier integrity in several tissues, including the lung and the brain. We have exploited the 'leakage-resistant' phenotype of Src-knockout mice to examine the characteristics of tumor growth and lung metastasis. These studies have revealed that the Src defect in VEGF-induced VP in the host tissue (i.e.blood vessels) provides protection from lung metastases. In the brain, a reduction in VEGF-induced VP is also associated with Src- mediated changes in FAK phosphorylation. Recent data indicates that FAK protein is enriched in brain blood vessels compared to surrounding cell types, and is a direct target of Src mediated VP. Therefore, we hypothesize that FAK is a key intermediate in the maintenance of the integrity of the BBB.
In Aim 1 we will characterize the role of Src in regulating VEGF-induced FAK activation and VP of brain blood vessels. These studies on Src and FAK are the basis to examine the molecular basis for the VP phenotype of two additional signaling intermediates (i.e.BMK1 and eNOS).
In Aim 2 we will determine whether Src regulates BMK1 in VEGF-stimulated brain blood vessels.
In Aim 3 we examine the functional role of eNOS in Src- vs. BMK1- mediated VEGF-induced VP. While these studies will provide novel and important insights in the regulation of the BBB, relatively few studies have examined the role of the BBB in brain tumors and metastases. Therefore, we will use animal models to determine the function of FAK, BMK1 and eNOS in the host compartment during tumor metastasis to the brain. These studies will build upon our previous studies of the role of Src-mediated metastases to the lung and provide the foundation to examine the growth and invasion of a panel of human astrocytomas. The results of these animal studies will be validated in human brain tumor samples to determine the clinicopathological relevance of VP and the BBB in tumor growth and invasion. PERFORMANCE SITE ========================================Section End===========================================
Showing the most recent 10 out of 26 publications
