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。我们的目标是确定内耳毛细胞和SGN是否可以更换后，这种损失。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学策略鉴定具有经历“功能转换”或分化以承担HC和SGN功能的潜能的成体干细胞（SC）类型。2)利用电生理和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的转导和电导组装中的功能和细胞事件链。4)使用电场（EF）通过SGN/SC促进感觉上皮中HC的整合/神经支配，并确定SC整合的潜在细胞机制。5)最后，通过在内耳中移植SC来改善听力受损动物模型。这些研究超越了内耳特定功能和再生。由于内耳所使用的机制可以通过其他信号转导系统以不同的形式表达，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。我们收集了令人信服的试验数据，以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转变，并为未来的治疗提供了一个预演。 公共卫生相关性：毛细胞（HCs）是终末分化的细胞，在内耳中将声音和平衡信号转换为电脉冲，具有显着的精度和灵敏度。一旦HC由于噪音、耳毒性药物或衰老而丢失，就没有有效的方法来刺激它们在成熟的内耳中再生。我们的长期目标是刺激毛细胞和/或鉴定能够重新填充哺乳动物内耳的成体干细胞，并使毛细胞的功能神经支配的神经元。

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. PUBLIC HEALTH RELEVANCE: Hair cells (HCs) are terminally-differentiated cells and convert sound and balance signals into electrical impulses in the inner ear, with remarkable precision and sensitivity. Once HCs are lost due to noise, ototoxic drugs or aging, there is no effective way to stimulate their regeneration in mature inner ears. Our long-term goal is to stimulate HCs and/or identify adult stem cells capable of re-populating the mammalian inner ear and to enable the functional innervations of HCs by neurons.