Re-population of Hair Cells and Spiral Ganglia Neurons

描述（由申请人提供）：我们研究的总体目标是确定毛细胞（HC）和螺旋神经节神经元（SGN）再生和突触形成的潜在细胞机制。hc和sgn可因耳毒性药物、衰老和/或遗传功能障碍的影响而丢失。我们的目的是确定内耳hc和sgn是否可以在这种损失后被替换。我们还试图了解内耳的再生过程，并确定大脑中具有类似于hc和sgn特性的增殖细胞类型。本研究的具体目的是：1)利用生物化学、分子生物学和生物物理策略，鉴定具有“功能开关”或分化潜能的成体干细胞（SC）类型，以承担hc和sgn的功能。2)利用电生理生化指标确定再生过程中HC-SGN突触形成的细胞机制。3)识别功能性hc和sgn的转导和电导组合中的功能和细胞链事件。4)利用电场（EFs）促进sgn /SCs在感觉上皮中的整合/神经支配，并确定SC整合的潜在细胞机制。5)最后，通过内耳移植SCs改善耳聋动物模型的听力。这些研究超越了内耳的特定功能和再生。由于内耳使用的机制可能通过其他信号转导系统以不同的形式表达，因此这些研究可能为神经系统中的SC分化，信号传导和整合提供新的见解。我们已经收集了令人信服的试点数据来证明这些研究的可行性。因此，这项研究可能代表了一种范式的转变，并作为未来治疗的预演。

DESCRIPTION (provided by applicant): The overall goal of our research is to identify the underlying cellular mechanisms of hair cell (HC) and spiral ganglia neuron (SGN) regeneration and synapse formation. HCs and SGNs can be lost from the effects of ototoxic drugs, aging and/or genetic dysfunction. We aim to determine whether inner ear HCs and SGNs can be replaced after such loss. We also seek to understand the regenerative process of the inner ear and to identify proliferative cell types in the brain with properties similar to HCs and SGNs. The specific aims of the study are to: 1) Identify adult stem cell (SC) types that have the potential to undergo "functional switch" or differentiation to assume the functions of HCs and SGNs using biochemical, molecular biology and biophysical strategies. 2) Determine the cellular mechanisms of HC-SGN synapse formation during regeneration using electrophysiological and biochemical indexes. 3) Identify the functional and cellular chain of events in the assemblage of transduction and electrical conductances for functional HCs and SGNs. 4) Promote the integration/innervations of HCs in the sensory epithelia by SGNs/SCs using electric fields (EFs) and to determine the underlying cellular mechanisms of SC integration. 5) Finally, improve hearing in a deafened animal model by engrafting SCs in the inner ear. These studies transcend inner ear-specific functions and regeneration. Since the mechanisms used by the inner ear may be expressed in different forms by other signal transduction systems, these studies may provide novel insights into SC differentiation, signaling and integration in the nervous system. We have collected convincing pilot data to show the feasibility of these studies. Thus, the study may represent a paradigm shift, and serve as a dry run for future therapy.