Investigating deskmoplakin during vasculogenesis

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DESCRIPTION (provided by applicant): DP is a key component of cellular adhesion junctions known as desmosomes; however, recent investigations have demonstrated a novel location for DP in junctions separate from desmosomes termed complexes adherens junctions. These junctions are found at contact sites between endothelial cells that line capillaries. Few studies have focused on the function of DP in de novo capillary formation (vasculogenesis) and branching (angiogenesis) during development or tumorigenesis. Only recently have investigations begun to determine the affect the loss of DP has on capillaries during embryogenesis (i.e., in DP-/- mice). Consequently, the goal of the proposed research is to determine the function of DP in complexus adherens junctions during capillary formation in embryos and tumors, and apply that knowledge to inhibiting tumor growth. Preliminary evidence shows that the loss of desmoplakin both in vivo and in vitro results in leaky capillaries and/or capillary destabilization (Gallicano et al., 2001). Tumorigenesis, like embryogenesis, is highly reliant on both vasculogenesis and angiogenesis. Without capillaries, an embryo fails to develop. Likewise, without capillaries a tumor also fails to develop or undergoes necrosis if already formed. Based on evidence described in this proposal, it is hypothesize that under strict regulation by an inducible promoter either ablation of, or mutation of, DP in endothelial cells lining capillaries will result in tumor inhibition or necrosis (if already formed) due to the disruption of the capillary network. Three Specific Aims are proposed to test this hypothesis. Using recently introduced tools and experimental approaches, it will be possible to identify distinct defects during development and to manipulate activation or repression of DP function within the embryo (as well as in tumors) followed by assessment of their effects on capillary formation and structure. The knowledge gained from this research will provide novel insights into vasculo- and angiogenesis during developmental and tumor growth and possibly provide novel approaches for inhibiting tumorigenesis.