Over the past several years, our group has been focused on studying genes with neuromodulatory, neuroprotective and/or neuroregenerative effects in models of neurodegeneration and neurotoxicity. We primarily have examined how the MANF/CDNF protein family can improve neuronal survival during injury or disease states. We previously published a study last year describing the neuroprotective actions of MANF against ischemic brain injury. We are continuing to explore the neuroprotective and neuroregenerative mechanism(s) MANF and CDNF. We are preparing a manuscript describing the function of MANF in C. elegans as it relates to cellular stress, specifically, endoplasmic reticulum stress. The phenomenon of ER stress occurs in many diseases beyond neurodegenerative and understanding its role may lead to broader therapeutic strategies for MANF and CDNF. Toward understanding ER stress, we developed a method that uses two different bioluminescent proteins in combination to concurrently monitor endoplasmic reticulum stress and calcium homeostasis. Our study published in PLOS ONE enables us to study how these cellular processes change in neurodegeneration and other diseases. To aid in our evaluation of gene therapy approaches to Parkinsons disease, we established a method to monitor changes in gait of rats that have Parkinsonian lesions. This work will aid in evaluating potential the therapeutics and has been published in Cell Transplantation. In addition to studying gene function and evaluating therapeutic potential of genes in models of neurodegeneration, we also work on improving and developing gene delivery technology. We have published several studies that highlight our approaches. For example, we conducted a study to assess the stability of AAV vectors and established method for safely inactivating AAV vectors in the laboratory. Our findings are published in Human Gene Therapy Methods. In collaboration with Bruce Hope at the NIDA IRP, we are working on alternative approaches to modifying neuronal activity. We published a paper characterizing how nanoparticle properties effect their uptake by neurons. We also examined how focused ultrasound can be used to permeabilize the blood brain barrier and promote systemic delivery of viral vectors into the brain. This work was a collaborative project with Mark Borden at CU Boulder and published in Theranostics. We describe the characterization and development of multiple transgenic tools that express a near-infrared fluorescent protein (IRFP) in neurons as a reporter of transgene expression. The longer wavelength of light used for visualization offers many advantages over other fluorescent reporters used for neuroscience applications. This work is published in J Neuroscience Methods. In collaboration with Yun Wang (NHRI, Taiwan) we demonstrate how 9-cis retinoic acid promotes neurorepair through the action of trophic factors and improves the recovery from an ischemic injury in a rat model of stroke.
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