TISSUE ENGINEERING IN THE INNER EAR

描述（由申请人提供）：在过去的十年中，我们和其他人已经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提高螺旋神经节细胞（SGC）的存活率和周围突起的再生长。我们提出的研究是针对这些“组织工程”的治疗干预的目标战略的进一步发展，创造的知识和技术来干预和影响被破坏的听觉系统，提供最佳的环境，重新引入听觉信息。利用我们实验室和其他实验室收集的数据，我们构建了一个耳聋后SGC病理生理学模型。该模型的原则定义了我们的实验目标-评估治疗类型对获益程度的影响，表征多个因素之间的相互作用以提高治疗效果，评估有前途的胚胎生长因子，并启动干细胞研究以替代听神经。我们的第一个具体目标（SA）测试的假设，即通过外源性神经营养因子输注或慢性刺激，将更有效地提高外周过程的生长和电反应性比抗氧化剂，其主要作用是通过逮捕/抑制凋亡级联的替代失去的营养支持。我们的第二个SA是由以下假设驱动的：正常存活反映了在细胞存活途径中在多个水平上起作用的多个因素的协同相互作用，并且多因素治疗将产生累加和协同效应。我们的第三个SA评估的假设，在压力，成熟的听觉细胞生化退化，成为最有效的发展过程中的因素作出反应。为此，我们很幸运能够获得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“替代”，将干细胞植入物作为替代听神经的手段的功效描述为特征。这些体内研究将为技术转移到人体应用提供关键步骤。所开发的干预措施不仅将在不久的将来直接改善人工耳蜗植入功能，而且还将提供预防听力耳朵神经性耳聋的干预措施，以及在更遥远的将来将再生毛细胞重新连接到中枢神经系统所必需的基质。

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.