MOLECULAR CLONING AND EXPRESSION OF MIDKINE RECEPTOR

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The long term aim of the proposed research is to define the molecular structure and function of the midkine signal transduction pathway which regulates cellular proliferation and differentiation Special emphasis in this effort is placed on the molecular cloning of the cell surface Midkine signal transduction receptor which we have recently identify from a Wilms~ tumor cell line using biochemical techniques. Recent studies have established the importance of Midkine expression in Wilms~ tumor, renal cell carcinoma and lung, colon and hepatocellular carcinoma. Our studies have also shown Midkine expression in autosomal dominant polycystic kidney disease (ADPKD) and its role as an important mediator in epithelial differentiation during kidney organogenesis. Our hypothesis is that Midkine functions as an autocrine or paracrine which regulates several biological processes including the growth regulation of epithelial cells in ADPKD as well as in oncogenic transformation in Wilms~ tumor and in differential mechanisms which regulate epithelial conversion of renal progenitor cells during renal development. We plan to clone Midkine receptor gene using either an expression cloning approach or ligand affinity chromatography to purify the MK receptor protein. Additionally, we also plan to examine Midkine signal transduction pathway, then define the basic developmental pattern in the kidney of expression of all identified components of the midkine signal transduction pathway including expression of the Midkine receptor in relation to its ligand.