TISSUE ENGINEERING IN THE INNER EAR

描述(申请人提供)：在过去的十年里，我们和其他人证明了通过外源性神经营养因子或恢复神经元的电活动来改善耳聋后螺旋神经节细胞(SGC)的存活和外周突起再生。我们建议的研究旨在进一步发展这些“组织工程”策略，以达到治疗干预的目的，创造干预和影响听力系统的知识和技术，提供重新引入听觉信息的最佳环境。利用本实验室和其他实验室收集的数据，我们构建了SGC耳聋后的病理生理学模型。这个模型的原则定义了我们的实验目标--评估治疗类型对所获得的益处程度的影响，描述多种因素之间的相互作用以提高治疗效果，评估有希望的胚胎生长因子，并启动一项干细胞研究以取代听神经。我们的第一个特定目标(SA)测试了这样一个假设，即通过外源性神经营养素输注或慢性刺激来替代失去的营养支持，将比抗氧化剂更有效地增强外周突起的生长和电反应，抗氧化剂的主要作用是通过阻止/抑制凋亡级联反应。我们的第二个SA是由这样的假设驱动的，即正常生存反映了在细胞生存路径的多个水平上作用的多个因素的协同作用，并且多因素治疗将产生相加和协同效应。我们的第三个SA评估了这一假设，即在应激期间，成熟的听觉细胞以生物化学的方式退化，对发育过程中最有效的因素做出反应。为此，我们幸运地获得了一种新的耳囊衍生因子。在第四个SA中，我们将SGC治疗的视野从“保护”扩展到“替换”，描述了干细胞移植作为替代听神经的一种手段的有效性。这些体内研究将为技术转移到人类应用提供关键的一步。开发的干预措施不仅将提供在不久的将来直接改善人工耳蜗功能的治疗，还将提供预防听力神经性耳聋的干预措施，以及在更遥远的未来将再生毛细胞重新连接到中枢神经系统所必需的底物。

DESCRIPTION (provided by applicant): In the last decade, we and others have demonstrated the improvement of spiral ganglion cell (SGC) survival and peripheral process regrowth post-deafening by exogenous neurotrophic factors or restoring electrical activity to neurons. Our proposed studies are directed at the further development of these "tissue engineering" strategies with the goal of therapeutic intervention, creating the knowledge and technology to intervene and influence the deafened auditory system, providing the optimal environment to re-introduce auditory information. Using data collected in our laboratory and others, we have constructed a model of SGC pathophysiology post-deafening. The tenets of this model define our experimental aims - to assess the influence of treatment type on the degree of benefit achieved, characterize the interaction between multiple factors to increase treatment efficacy, evaluate promising embryological growth factors, and initiate a stem cell study to replace the auditory nerve. Our first specific aim (SA) tests the hypothesis that replacement of lost trophic support, via exogenous neurotrophin infusion or chronic stimulation, will be more efficacious in enhancing peripheral process outgrowth and electrical responsiveness than will antioxidants, whose primary action is through the arrest/inhibition of the apoptotic cascade. Our second SA is driven by the hypothesis that normal survival reflects the synergistic interaction of multiple factors that act at a number of levels in the cell survival pathways, and that multi-factor treatment will yield additive and synergistic effects. Our third SA assesses the hypothesis that during stress, mature auditory ceils regress biochemically, becoming responsive to factors most effective during development. For this aim we are fortunate to have access to a novel otocyst derived factor. In the fourth SA, we expand our vision of SGC treatments from "protection" to "replacement," characterizing the efficacy of stem cell implants as a means to replace the auditory nerve. These in vivo studies will provide a critical step in the technology transfer to human application. The interventions that are developed will provide not only treatments that will directly improve cochlear implant function in the near future, but also, interventions to prevent nerve deafness in hearing ears, and the substrate essential for reconnecting regenerated hair cells to the central nervous system in the more distant future.