CNS specific Knock-out and Multidrug Transport

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DESCRIPTION (provided by applicant): Development of transgenic animals with MDR1 gene deletions (null mutation) in all tissues, has provided limited understanding of biologic and transport functions of MDR1 product, P-glycoprotein or Pgp in modulating efficacy and toxicity of a broad range of drugs. However, mice with null mutations are not able to precisely clarify the role of transporters in dictating drug availability to the CNS*. Also, clinical studies with Pgp inhibitors such as PSC833 in cancer patients suggest that global inhibition of Pgp function also enhances dose-limiting toxicity in periphery, due to expression of Pgp in the major organs of drug absorption and drug elimination. To elucidate tissue-specific transport mechanisms without the confounding and often counteracting transport and elimination actions encountered by the same drug in other tissues, such as liver, kidney and gut, a more precise animal model system is required. Therefore, the goal of this proposal is to develop an animal model system that allows selective shut-down of a well-described drug transporter, MDR1 in CNS to directly elucidate and quantify the functional role of drug transporters in delivery and disposition of drug in the CNS. The central hypothesis of this R21 exploratory grant proposal is as follows: Tissue-specific abrogation of MDR1 expression at the blood-cerebral spinal fluid and blood-brain barrier, and in the CNS, without compromising other tissues, will enhance drug availability in the brain. We will test this hypothesis using the following aims: Aim 1: To develop a transgenic mouse model depleted of the MDR1 product, Pgp, only in CNS tissues. This will be accomplished by (a) identifying a CNS-specific promoter suitable for use in developing a brain-specific tissue knockout system, and (b) with the optimized promoter selected, the tissue-specific MDR1 knockout system will be developed and validated; Aim 2: To compare transport and disposition of probe substrates in CNS-specific vs. whole animal MDR1 knockout systems. With the proposed studies, we will develop a CNS-specific knockout mouse model that would allow quantitative and definitive estimates of the MDR1 product, Pgp, in delivery and disposition of drugs across the therapeutic spectrum. Availability of such an experimental model will provide a tool for studies of other biological and neurological processes specific to CNS. This tool could become an indispensable one to study CNS proteins that express in multiple tissues throughout the body. The potential benefits to overall biomedical research outweigh the calculated risks associated with this exploratory research.