Regeneration in the olfactory system

描述（由申请人提供）：外周哺乳动物嗅上皮是一种动态组织，其中包含能够在损伤或病理反应中产生新的感觉神经元的干细胞。我们最近确定，即使在非常老的动物身上，这种再生能力仍然很强。这就提出了几个关于嗅觉系统及其独特的神经元再生能力的关键问题。这些老的干细胞能够产生正常功能的神经元吗？它们如何决定表达哪些受体基因，因为这些受体基因在动物生命的不同阶段是不同的？这些新的神经元是如何整合到旧的组织和嗅球的现有电路中去的？我们建议使用一种遗传策略，其中白喉毒素受体在OMP+成熟嗅觉感觉神经元中特异性表达。注射白喉毒素后，只有那些表达受体的细胞会被杀死，导致OSN群体的病变，上皮或目标嗅球中的其他细胞很少或没有附带损伤。这使我们能够在正常但年老的动物中检查新神经上皮的再生。这些实验将提供深入了解组织老化过程和老年动物新嗅觉系统的重建。我们希望获得对神经元增殖的理解，这将使我们能够想象在许多病理和正常衰老过程中补偿神经退行性损失的方法。此外，它可能提出改善老年人嗅觉的策略，从而扭转这一人群普遍存在的营养不良和生活质量低下的问题。

DESCRIPTION (provided by applicant): The peripheral mammalian olfactory epithelium is a dynamic tissue that contains stem cells capable of generating new sensory neurons in response to injury or pathology. We have recently determined that this regenerative capacity remains robust even in very old animals. This raises several critical questions about the olfactory system and its unique capacity to regenerate neurons. Are these older stem cells capable of generating normal functioning neurons? How do they determine which receptor genes to express, as these differ at different stages of an animal's life? How do these new neurons integrate into an older established tissue and the existing circuitry of the olfactory bulb? We have proposed to use a genetic strategy in which the Diphtheria toxin receptor is expressed specifically in OMP+ mature olfactory sensory neurons. Upon injection of the diphtheria toxin only those cells expressing the receptor will be killed, resulting in a lesion of the OSN population with little or no collateral damage to other cells in the epithelium or in the target olfactory bulb. This allows us to examine the re-growth of a new neuroepithelium in an otherwise normal, but older animal. These experiments will provide insight into the tissue aging process and into the reconstitution of a new olfactory system in aged animals. We hope to gain an understanding of neuronal proliferation that will allow us to imagine ways to compensate for neurodegenerative losses in numerous pathologies and over the course of normal aging. Additionally it may suggest strategies for improving the olfactory sense in the aged, thereby reversing the poor nutrition and quality of life common to this population.