Research Project
9477593
Project Summary Cocaine addiction is a complex, destructive, and often chronic disorder that is difficult to treat. Among the main challenges for treatment are heightened craving and relapse to drug use after extended periods of abstinence. Currently, there are no FDA-approved medications for safe and effective treatment of cocaine addiction. Stem cell-based therapy using mesenchymal stem cells (MSCs) has emerged as a novel and successful approach for the treatment of various brain pathologies. MSCs can home to pathological areas in the brain, release growth factors, and serve as cellular delivery tools in various brain disorders. Moreover, restoration of basal glutamate levels via the glutamate transporter (EAAT) has been proposed as a promising target for treatment of drug dependence. Therefore, MSCs differentiated to express EAATs may have a combined, long-term effect that can attenuate cocaine craving and relapse. However, a critical problem for implementation of stem cell-based therapy is the lack of reliable, non-invasive means for imaging and tracing cells within deep brain structures, and evaluating their functionality, bio-distribution and final fate. We have developed a novel gold nanoparticle (GNP)-based CT imaging technique for real time, longitudinal and non-invasive tracking and imaging of cells within the brain. This technique includes a unique, quantitative non-invasive CT ruler that can be used in humans, to extrapolate the exact number of GNP-loaded cells within each brain region in a non-destructive manner, and thus to determine the cell dose needed. In this proposal, our goal is to examine EAAT-expressing MSCs loaded with GNPs as a novel approach for cocaine addiction therapy. In the first aim, MSCs will be differentiated to express EAATs and loaded with GNPs, and intranasally administered to rats. We will examine the long-term therapeutic impact on cue- induced cocaine seeking in the incubation of craving model, in correlation with longitudinal in- vivo determination of cell migration and final fate. In our second aim, we will identify potential factors in the brain that correlate with the behavioral effect of treatment. Such factors can further optimize the efficacy of our suggested treatment, as MSCs can be specifically designed for on-demand, controlled release of therapeutics at the specific regions to which the cells navigate. Cocaine addiction affects neurogenesis, and may involve various factors such as miRNAs, which affect EAAT expression. Therefore, we will analyze alterations in specific miRNAs (using Nanostring nCounter assay, a cutting-edge profiling technology), and BDNF, IL-10 and EAAT expression levels in the main regions to which the nMSCs homed (preliminary results show the dentate gyrus, ventral tegmental area, nucleus accumbens and prefrontal cortex), in correlation with neurogenesis (in the dentate gyrus). We anticipate that this innovative research will lay the groundwork for further studies of MSCs for treatment of drug addiction.
