Molecular Biology of Olfactory Receptor Genes

描述(申请人提供)：我们感兴趣的是利用小鼠作为实验系统来阐明哺乳动物嗅觉辨别的潜在机制。小鼠嗅觉系统的显著辨别能力取决于1000个气味受体(OR)基因的大家族。我们正在研究单个神经元如何具体选择只表达数千个不同的OR基因中的一个等位基因。这种OR基因选择机制对嗅觉歧视至关重要。在之前的资助期间，我们加深了对OR基因调控的了解，发现了一种意想不到的令人兴奋的基因调控新机制。我们已经证明，除了OR基因外，对免疫系统至关重要的基因家族也是异步复制的。我们最引人注目的数据表明，OR基因和其他常染色体基因的这种复制异步性在不同染色体的长距离上存在协调。根据我们之前的观察，这项资助的具体目的是：1.分析小鼠7号染色体上P2OR基因簇的等位基因特异性表观遗传学变化。这些研究将包括生化和分子方法来研究OR基因的染色质结构，并将利用现有的转基因小鼠。2.通过研究常染色体非整倍体对OR基因调控的影响，研究与X失活的平行关系。3.确定最终将产生成熟嗅觉神经元的前体细胞是否已经选择了它们将表达的OR基因。了解这些机制将有助于理解嗅觉歧视是如何发生的，并有助于理解基因表达的调节如何允许嗅觉神经元以及其他神经元的显着多样性。

DESCRIPTION (provided by applicant): We are interested in elucidating the mechanisms underlying olfactory sensory discrimination in mammals using the mouse as an experimental system. The remarkable discriminatory ability of the mouse olfactory system depends on a large family of 1,000 odorant receptor (OR) genes. We are studying how individual neurons specifically choose to express only one allele of the thousand distinct OR genes. This OR gene choice mechanism is of central importance to olfactory discrimination. In the previous funding period, we have advanced our knowledge of OR gene regulation and have discovered an unanticipated and exciting new mechanism of gene regulation. We have shown that in addition to OR genes, gene families essential to the immune system are asynchronously replicating. Our most striking data indicate that there is coordination along long distances of various chromosomes of this replication asynchrony of OR genes and other autosomal genes. Following on our previous observations, the specific aims of this grant are to: 1. Analyze allele-specific epigenetic changes at the P2OR gene cluster on mouse chromosome 7. These studies will include biochemical and molecular approaches to studying chromatin structure of OR genes and will take advantage of existing transgenic mice. 2. Study parallels to X-inactivation by studying the effects of aneuploidy of autosomes on OR gene regulation. 3. Determine whether the precursor cells that will ultimately give rise to mature olfactory neurons have already chosen the OR gene they will express. Understanding these mechanisms will be of value in understanding how olfactory discrimination occurs and in understanding how the regulation of gene expression allows for the remarkable diversity of olfactory neurons and perhaps other neurons.