? Cisplatin is an effective antineoplastic drug for the treatment of solid tumors, although its clinical use is often limited because of adverse effects on renal function. This side effect often delays or precludes subsequent chemotherapy cycles, thereby reducing the overall antineoplastic efficacy of cisplatin. Preliminary data demonstrate that mice lacking the renal drug transporter Mrp2 have an increased susceptibility to cisplatin nephrotoxicity. In addition, Mrp2 is induced in the kidneys of cisplatin-treated wild-type mice likely as a compensatory mechanism to enhance clearance of subsequent chemotherapy cycles. Experiments in this proposal will test the hypothesis that Mrp2 is critical for the disposition of cisplatin and prevention of cisplatin nephrotoxicity. Furthermore, it is hypothesized that the inducible expression of Mrp2 is regulated by the transcription factor Nrf2. During the mentored phase (Specific Aim 1), the P.I. will determine the in vivo contribution of Mrp2 to the renal disposition and toxicity of cisplatin using Mrp2-null mice. Additional activities during the mentored phase will include training on a number of techniques that are required for completion of Specific Aims 2 and 3 during the independent award phase.
In Specific Aim 2, the P.I. will establish which single nucleotide polymorphisms in human MRP2 influence transport of cisplatin conjugates and cisplatin cytotoxicity using an in vitro overexpression system.
In Specific Aim 3, the P.I. will determine the role of Nrf2 in the compensatory induction of Mrp2 during cisplatin injury using Nrf2-null mice and in vitro ChIP assays. The work proposed in this grant will serve as the foundation for transition into an independent investigator at an academic research institution in the next two years. The mentored phase (K99) will occur at the University of Kansas Medical Center under the guidance of Dr. Curtis Klaassen. The proposed studies are expected to reveal the role of Mrp2 in protecting the kidneys from cisplatin toxicity. ? PUBLIC HEALTH RELRVANCE: Understanding how transporters can protect different organs from chemotherapy-related adverse events will directly impact human health by enabling the development of screening mechanisms that predict drug-drug interactions and detect polymorphisms that increase the susceptibility of patients to toxic side effects. Furthermore, these studies will contribute to our understanding of the adaptive mechanisms that occur within the kidneys in response to drug toxicity. ? ?
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