Tumor cells can acquire broad multidrug resistance (MDR) to a variety of chemically and structurally unrelated chemotherapeutic agents. The MDR phenotype is associated with the over-expression of drug efflux pumps such as the P-glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP); however, there is evidence from both in vitro and clinical studies for additional mechanisms for MDR. For example, over-expression of the Lung-Resistance Protein (LRP) in lung cancer cell lines is correlated with MDR. Recently, it was shown that LRP is the human homologue of the major vault protein, a structural component of the novel vault ribonucleoprotein particle (RNP). Vaults are large elaborate structures, nearly three times the size of a ribosome and ten-fold larger than the signal recognition particle. They are so-named because their complex morphology resembles the vaulted ceiling of a medieval cathedral. Vaults are over-expressed in non-Pgp or non-MRP cell lines; and, expression of the major vault protein (MVP) is associated with a poor prognosis in acute myeloid leukemia and advanced ovarian carcinoma. Vaults are present in thousands of copies per cell and are conserved from slime molds to humans. The long term goal of this work is to identify the cellular processes that require the vault RNP and to understand how these functions affect the development of a multicellular organism in order that we understand the mechanisms underlying multidrug resistance. We will initiate a biochemical, cellular, genetic and molecular analysis of vault-associated proteins in the nematode, C. elegans. The investigation of vaults in a cellular and developmental context will help reveal the full range of the vault function and may provide insight into the logic that underlies the structural complexity of the vault complex and the acquisition of multidrug resistance. This is a collaborative research project between a junior and senior faculty member. Each will receive reciprocal training and mentoring in their complementary fields of cellular biochemistry and molecular genetics. New research training will be obtained in sophisticated areas of genomics and proteomics as well as advanced imaging techniques for light microscopy.
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