Gene Therapy And Neurodegeneration

在过去的几年里，我们的团队一直专注于研究神经退行性疾病和神经毒性模型中具有神经调节，神经保护和/或神经再生作用的基因。 作为巴里霍弗博士（NIDA）和马特萨尔玛（U赫尔辛基）的主要项目合作的一部分，我们研究了保守的多巴胺能神经营养因子（CDNF）在帕金森病小鼠模型中的神经保护作用。 我们已经发现，CDNF蛋白可以赋予神经保护和神经再生对多巴胺能神经元毒素，MPTP引起的神经毒性。 描述本研究的手稿已被Cell Transplantation接受发表。 我们还在研究CDNF的同源物，中脑星形胶质细胞衍生神经营养因子（MANF）。 我们去年发表了一项研究，描述了MANF对缺血性脑损伤的神经保护作用。 我们正在继续探索神经保护和神经再生机制MANF/CDNF。 为了实现这个目标，我们正在准备一份手稿，描述MANF在C中的功能。因为它涉及细胞应激，特别是内质网（ER）应激。 ER应激现象发生在神经退行性疾病以外的许多疾病中，了解其作用可能会导致MANF和CDNF更广泛的治疗策略。 除了我们与C。elegans的研究，我们已经建立了几种新的试剂，用于研究内质网应激中MANF的结构/功能关系。 使用表达MANF和绿色荧光蛋白（GFP）的融合蛋白的稳定细胞系，我们已经鉴定了对其定位/分泌重要的蛋白质区域。 使用我们在过去一年中建立的工具，我们将专注于了解MANF在细胞中的功能。 我们的部分先前已经证明了骨形态发生蛋白7（BMP 7）促进神经再生的能力。 作为这项工作的延续，我们使用了原代皮层神经元的体外模型来表明BMP 7改变了轴突和树突的外观，并将其与细胞外基质蛋白的变化联系起来。 我们正在为出版准备手稿。 除了神经营养因子，我们已经完成了一项研究，检查谷氨酸转运蛋白（GLT 1）的能力，以减少谷氨酸的毒性作用，使用啮齿动物模型的中风。 我们产生了表达GLT 1基因的腺相关载体，并证明它可以增加缺血事件引起的大脑中谷氨酸的清除。 这与缺血后行为恢复增加和组织损伤减少相关。 研究结果发表在PLoSONE上，强调了中风后急性缺血诱导的谷氨酸溢出的重要性。 CT正在进行中。

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. As part of a collaboration on a primary project of Dr. Barry Hoffer (NIDA) and Mart Saarma (U Helsinki), we have examined the neuroprotective effects of conserved dopaminergic neurotrophic factor (CDNF) in an mouse model of Parkinsons disease. We have found that CDNF protein can confer neuroprotection and neuroregeneration against neurotoxicity caused by the dopaminergic neuron toxin, MPTP. The manuscript describing this study has been accepted for publication at Cell Transplantation. We are also working on the homolog to CDNF, mesencephalic astrocyted derived neurotrophic factor (MANF). We 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/CDNF. Towards this goal, we are preparing a manuscript describing the function of MANF in C. elegans as it relates to cellular stress, specifically, endoplasmic reticulum (ER) 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. In addition to our work with C. elegans, we have established several novel reagents for studying the structure/function relationship of MANF in ER stress. Using stable cell lines expressing a fusion proteins of MANF and green fluorescent protein (GFP), we have identified a region of the protein important for its localization/secretion. Using the tools weve built over the past year, we will focus on understanding MANFs function in the cell. Our section has previously demonstrated the ability of Bone Morphogenetic Protein 7 (BMP7) to promote neuroregeneration. As a continuation of this work, we have used an in vitro model of primary cortical neurons to show that BMP7 changes the appearance of axons and dendrites and have linked this to the change in extracellular matrix proteins. We are preparing the manuscript for publication. In addition to neurotrophic factors, we have completed a study examining the ability of the glutamate transporter (GLT1) to reduce the toxic effects of glutamate using an rodent model of stroke. We generated an adeno-associated vector expressing the GLT1 gene and demonstrated it could increase glutamate clearance in the brain caused by an ischemic event. This correlated with increased behavioral recovery and decreased tissue damage following ischemia. The results were published in PLoSONE and emphasize the importance of targeting ischemia-induced glutamate overflow acutely following stroke. ct is ongoing.