Genomics of Olfactory Regeneration

描述(申请人提供)：哺乳动物嗅觉上皮的感觉神经元可以再生，即使它们被完全消除。这种能力贯穿动物的一生，对基础神经科学和应用神经科学研究都具有重要意义。它的作用机制被认为与寻找神经退行性疾病和神经系统创伤的促进再生疗法有关。为了扩大我们对嗅觉再生的理解，我们已经确定了1260个转录本，它们在嗅球切除后嗅觉上皮内的丰度会发生变化，这一操作会导致嗅觉感觉神经元的选择性死亡和随后的再生。在这些转录本中，303个与感觉神经元前体细胞的增殖同时增加。这303个转录本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与嗅觉再生有关。在这一应用中，我们建议将重点放在可能对嗅觉感觉神经元的增殖和分化至关重要的基因产物子集上。第一个具体目标是通过确定哪些细胞类型表达它们，包括与已知祖细胞类型的标记的空间和时间重叠，来确定每个转录本参与嗅觉再生的能力。第二和第三个目标进一步集中在有针对性缺失的一小部分基因上。这些目的是测试该基因的缺失是否会改变嗅觉上皮的发育或再生，从而导致行为、细胞或分子水平的改变。拟议中的实验将明确测试几种蛋白质是否对嗅觉再生是必不可少的，并将确定数十种额外蛋白质的潜在作用。

DESCRIPTION (provided by applicant): The sensory neurons of the mammalian olfactory epithelium can be regenerated even if they are completely eliminated. This capacity, which lasts throughout the life of the animal, 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. To extend our understanding of olfactory regeneration, we have identified 1,260 transcripts 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 transcripts, 303 increase contemporaneously with the proliferation of sensory neuron progenitors. The functions of the proteins encoded by these 303 transcripts 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. 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 transcript 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 small 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 behavioral, cellular, or molecular level. The proposed experiments will definitively test whether several proteins are dispensable for olfactory regeneration and will define the potential roles of a couple dozen additional proteins.