The endothelium plays a critical role in vascular homeostasis and response to injury. Work contributed by our laboratory during the previous funding term characterized the role of endothelial cells (EC) in novel inflammatory and procoagulant mechanisms. These studies also identified a novel anti-apoptosis molecule of the IAP gene family, designated survivin. Expressed in embryonic and fetal development, survivin is undetectable' in quiescent normal tissues and becomes abundantly re-expressed in all common human cancers, in vivo. Recently, we found that survivin is the first apoptosis inhibitor to date to be expressed in mitosis (02/M) in a cell cycle-dependent manner, and to localize to mitotic spindle microtubules of dividing cells. Moreover, growth factor stimulation of EC resulted in prominent expression of survivin during angiogenic responses, in vitro and in vivo. Therefore, the hypothesis that cell cycle expression of survivin may counteract apoptosis of proliferating EC during angiogenesis can be hypothesized, and will constitute the focus of this continuation application. In the first specific aim, we will characterize the spectrum of cytoprotection mediated by survivin in proliferating EC, in vitro and in vivo, and determine the effect of survivin targeting in models of angiogenesis. In the second specific aim, we will characterize the structure-function relationship of survivin- microtubule interaction and its cellular and molecular requirements for apoptosis inhibition in dividing EC. In the third specific aim, we will dissect the growth factor signaling pathway leading to survivin gene expression and identify mediators linking the control of EC proliferation to apoptosis inhibition. In continuity with the broad objectives the overall proposal is designed to elucidate a novel interface between EC proliferation and survival. These studies should provide important; insights for therapeutic manipulation of EC apoptosis during normal or aberrant (tumor) angiogenesis.
Showing the most recent 10 out of 108 publications
