The long term goals of the proposed research are to understand the mechanisms underlying regulation of normal and dysregulated cell growth in the vascular system and in neoplastic transformation. To achieve these goals, the laboratory has focused on the platelet-derived growth factor (PDGF) and its inducible cytokine pleiotrophin (PTN) as examples of important growth regulatory molecules. Both PDGF and PTN have different properties to suggest important roles in normal growth and to signal the abnormal growth patterns in the diseased vessel wall and in neoplasia; the similarities between the pathological processes in the vessel wall and neoplasia have suggested important model systems with which to study how PDGF and PTN function at the molecular level. This proposal focuses on PTN as a potential downstream mediator of PDGF. It builds upon preliminary data that establishes the requirement of an intact endogenous PTN signaling system for transformation of a human breast cancer cell line and molecular evidence that independent domains of PTN separately transform cells and promote angiogenesis. Unique models have been established to experimentally dissect the separate pathways that signal transformation and angiogenesis and will be exploited to lay the foundation to design new therapeutic approaches to control abnormal cell growth in man.
The Specific Aims are:
We aim to dissect and analyze the separate domains of pleiotrophin that are responsible for the transformed and angiogenic phenotypes and to use pleiotrophin dominant negative effectors to selectively reverse these phenotypes in vitro and in vivo.
We aim to seek the mechanisms by which pleiotrophin initiates its angiogenic signal.
We aim to analyze the effects of gain of function of PDGF A, of pleiotrophin, and the loss of function pleiotrophin dominant negative effector PTN 1-40 in the vascular system of transgenic mice. The significance of the proposed research is the development of understanding into mechanisms of the angiogenic switch to accelerate tumor growth and the identification of a molecule that is able to trigger the signaling cascade to establish the angiogenic phenotype and transformation and their potential to design therapy. Innovative model systems have been developed to achieve these results and to establish inhibitors of value of tumor cell growth both in vitro and in vivo. These model systems will be of benefit to others in the field.
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