A few cytosolic proteins that have been associated with injury repair, rheumatoid arthritis, restenosis and angiogenesis are selectively released from cells through a novel ER/Golgi-independent """"""""Protein Export"""""""" pathway. In fact, elevated levels of specific exported proteins have been detected in the blood and urine of cancer patients. Our goal is to develop a new class of therapeutically relevant drugs that selectively block """"""""export"""""""" of these proteins; thereby, dramatically reducing their extracellular bioavailability. We have established a relevant mammalian cell mutagenesis/expression system to characterize specific cellular components (drug targets) mediating protein export. We will identify critical peptide domains (trafficking signals) involved in regulating protein export from normal, activated or diseased cells. Once identified, peptide affinity chromatography will be used to purify the cognate cellular factor for subsequent characterization. We will identify therapeutically relevant small molecule drugs that interfere with interactions occurring between the exported protein and its cognate cellular factor; thereby, blocking its extracellular appearance. This innovative strategy will result in the identification of more specific, less toxic, anti cancer drugs than those currently in use.
The proposed experiments are designed in a manner that will lead to the development of a new class of therapeutic products blocking the highly selective release, """"""""export"""""""", of specific cytosolic proteins directly involved in unwanted cell growth (anti-proliferation), inflammation (rheumatoid arthritis), restenosis and tumor-dependent angiogenesis.
