Genomic of Olfactory Regeneration

嗅觉上皮的感觉神经元即使被完全消除，也可以再生。 这种能力持续整个动物的一生，对基础和应用都具有重要意义 神经科学研究。它的机制被推定与寻找再生有关- 促进神经退行性疾病和神经系统创伤的治疗。其作用机制 显然也与神经发育有关。为了扩大我们对嗅觉再生的理解，我们 已经确定了1205个mRNAs，它们在去除嗅觉上皮细胞后其丰度发生了变化 嗅球，一种导致选择性死亡和随后的嗅觉再生的操作 感觉神经元。在这些mrna中，303个与感官的增殖同时增加。 神经前体细胞。这303个mRNAs编码的蛋白质的功能预测了几个潜在的 过程，包括转录激活的细胞增殖和分化，上调细胞 周期、轴突生长和细胞信号。这些蛋白质中只有一小部分以前被认为与 嗅觉再生或发育。在这个应用中，我们建议关注基因产品的一个子集 这可能对嗅觉感觉神经元的增殖和分化至关重要。第一 具体目的是确定每种基因产物参与嗅觉再生的能力。 确定哪些细胞类型表达它们，包括与已知标记的空间和时间重叠 祖细胞类型。第二和第三个目标进一步集中在目标基因的子集上 删除部分可用。这些目的是测试基因的缺失是否会改变发育或 嗅觉上皮的再生，导致细胞或分子水平的变化。建议数 实验将明确测试几种蛋白质是否对嗅觉发育和 再生，并将确定几十个额外的蛋白质的潜在作用。

The sensory neurons of the olfactory epithelium can be regenerated even if they are completely eliminated. This capacity lasts throughout the life of the animal and is of significant interest for both basic and applied neuroscience research. Its mechanisms are presumed to be relevant to the search for regeneration- promoting therapies for neurodegenerative disorders and trauma of the nervous system. Its mechanisms are also clearly relevant to neural development. To extend our understanding of olfactory regeneration, we have identified 1,205 mRNAs whose abundance within the olfactory epithelium changes after removal of the olfactory bulbs, a manipulation that causes the selective death and subsequent regeneration of the olfactory sensory neurons. Of these mRNAs, 303 increase contemporaneously with the proliferation of sensory neuron progenitors. The functions of the proteins encoded by these 303 mRNAs predict several underlying processes, including transcriptional activation of cell proliferation and differentiation, up-regulation of the cell cycle, axon outgrowth, and cell signaling. Only a handful of these proteins have previously been linked to olfactory regeneration or development. In this application, we propose to focus on a subset of gene products that are likely to be critical for proliferation and differentiation of the olfactory sensory neurons. The first specific aim is to define the capacity for each gene product to be involved in olfactory regeneration by determining which cell types express them, including spatial and temporal overlap with markers of known progenitor cell types. The second and third aims focus further on a subset of genes for which targeted deletions are available. These aims test whether the absence of the gene alters the development or regeneration of the olfactory epithelium, leading to changes at the cellular or molecular level. The proposed experiments will definitively test whether several proteins are dispensable for olfactory development and regeneration, and will define the potential roles of a couple dozen additional proteins.