Genomics of Olfactory Regeneration

嗅觉再生的基因组学

• 批准号: 7094567
• 负责人: Timothy S McClintock
• 金额: $ 34.44万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094567
• 关键词: afferent nerve; biomarker; cell differentiation; cell proliferation; developmental neurobiology; gene deletion mutation; gene expression; genetic transcription; genetically modified animals; laboratory mouse; messenger RNA; microarray technology; nervous system regeneration; neurogenesis; neurogenetics; olfactory lobe; polymerase chain reaction; protein localization; protein structure function; receptor expression; respiratory epithelium; transcription factor

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.

描述（由申请人提供）：即使完全消除了哺乳动物嗅觉上皮的感觉神经元，也可以再生。这种能力在动物的整个生命中都持续，对于基本和应用神经科学研究都引起了重大关注。假定其机制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。为了扩展我们对嗅觉再生的理解，我们已经确定了1,260份成绩单，它们在去除嗅球后的嗅觉上皮变化中的丰度会发生变化，这种操作会导致选择性死亡，并随后再生嗅觉感觉神经元。在这些转录本中，303随着感觉神经元祖细胞的增殖而同时增加。由这303个转录本编码的蛋白质的功能预测了几个基本过程，包括细胞增殖和分化的转录激活，细胞周期的上调，轴突生长和细胞信号传导。以前只有少数这些蛋白质与嗅觉再生有关。在此应用中，我们建议专注于一部分基因产物，这些基因产物可能对嗅觉感觉神经元的增殖和分化至关重要。第一个具体目的是通过确定哪种细胞类型表达它们，包括与已知祖细胞类型的标记物相重叠，定义每个转录物与嗅觉再生有关的能力。第二和第三目的进一步集中在有针对性缺失的一小部分基因子集上。这些目的测试基因的缺失是否改变了嗅觉上皮的发展或再生，从而导致行为，细胞或分子水平的变化。提出的实验将确定测试几种蛋白是否可用于嗅觉再生，并将定义几十个额外的蛋白质的潜在作用。