Grant: Discovery Grants Program - Individual

Significance: One of the major problems in drug discovery for the central nervous system is designing drugs that are efficiently transported across the blood brain barrier with sufficient residency time for efficacy. This is true of many drugs that are being developed for neurodegenerative diseases. One mechanism to address this problem is to use transport systems that are active at the blood brain barrier as delivery systems. Proposal: Osmolytes and chaperones are the body's natural defense mechanism for maintaining protein structure under stress. The major osmolyte of the central nervous system (CNS) is myo-inositol, which is synthesized in situ or transported across the blood-brain barrier. Although known for over 25 years, the biochemical characterization and regulation of the myo-inositol co-transporter family is not well understood. In the previous granting period, we have garnered understanding of the specificity, structural limitations and location of sodium and proton myo-inositol transporters as a possible mechanism for controlled CNS drug delivery. In the present proposal, we will continue to characterize this family of transporters with respect to regulation of activity both at the blood-brain barrier and within the CNS on glial and neuronal populations. We will further investigate the possibility of utilizing this system for drug delivery based on the minimum binding motif that we have now identified or alternatively as a tether to pull impermeable drugs into the CNS. Objectives: 1. ) Characterize the regulation of SMIT1/2 and HMIT1 activity at the blood brain barrier and in CNS specific cell types. 2. ) Determine active transport of inositol-based compounds by SMIT1/2 and HMIT.