Glycoconjugates in Olfactory Cell-Cell Interactions

描述（由申请人提供）：本项目的主要目的是增加我们对感觉神经元轴突在发育和再生过程中的指导机制的理解。我们最近发现了一个基因，β-3-N-乙酰氨基葡萄糖转移酶（β-3GnT1），它是由嗅觉上皮细胞中的感觉神经元亚群表达的，也是由一些颅神经节和背根神经节中的感觉神经元表达的。它编码一种对终止于乳糖胺的聚糖合成至关重要的酶。β-3 GnT 1表达对于嗅球中嗅觉神经元的生长和引导到目标是必不可少的。初步证据表明，在β 3GnT 1基因无效突变的小鼠中，轴突导向受到严重干扰。我们将使用气味受体报告小鼠来表征主要嗅觉系统中β-3GnT1功能突变的丧失。我们还将分离和分析含有乳糖胺的蛋白质的结构。嗅觉组织包含称为半乳糖凝集素的蛋白质家族的成员，其结合乳糖胺，并且被认为通过这些含乳糖胺的蛋白质参与粘附和信号传导功能。我们将分析半乳糖凝集素与表达乳糖胺的嗅觉蛋白的结合，并研究半乳糖凝集素基因敲除小鼠的引导缺陷。此外，我们将分析主要嗅觉系统再生的独特能力，并确定乳糖胺/半乳糖凝集素相互作用在这一过程中发挥的作用。初步研究表明，犁鼻轴突的指导也受到干扰β-3GnT1突变小鼠，因此，我们将分析乳糖胺的犁鼻连接的发展中的作用，以副嗅球犁鼻受体报告小鼠。这些研究将揭示在感觉系统发育过程中共享的分子和机制，并进一步深入了解嗅觉感知的分子和细胞生物学，特别是损伤后嗅觉功能的恢复。项目叙述：该项目将揭示嗅觉系统发育所需的复杂聚糖的功能。此外，作为自发再生的模型，这些研究可能会扩大我们对周围神经损伤和神经退行性疾病的潜在治疗方法的理解。

DESCRIPTION (provided by applicant): The main objective of this project is to add to our understanding of the mechanisms underlying sensory neuron axon guidance during development and regeneration. We recently discovered a gene, beta-3-N-acetyl-glucosaminyltransferase (beta-3GnT1) that is expressed by subsets of sensory neurons in the olfactory epithelium but also by sensory neurons in some cranial ganglia and in dorsal root ganglia. It encodes an enzyme that is key to the synthesis of glycans that terminate in Lactosamine. Beta-3GnT1 expression is essential for the growth and guidance of olfactory neurons to targets in the olfactory bulb. Preliminary evidence suggests that axon guidance is severely perturbed in mice with a null mutation in their beta3GnT1 gene. We will characterize the loss of function mutations of beta-3GnT1 in the main olfactory system, using odorant receptor reporter mice. We will also isolate and analyze the structure of lactosamine containing proteins. Olfactory tissues contain members of a family of proteins called galectins that bind to Lactosamine and are thought to be involved in adhesive and signaling functions through these Lactosamine-containing proteins. We will analyze the binding of galectins to olfactory proteins that express Lactosamine and study guidance defects in galectin knockout mice. Furthermore we will analyze the unique ability of the main olfactory system to regenerate and to determine the role that Lactosamine/galectin interactions plays in this process. Preliminary studies show that vomeronasal axon guidance is also perturbed in beta-3GnT1 mutant mice, thus we will analyze the role of Lactosamine in development of vomeronasal connections to the accessory olfactory bulb using vomeronasal receptor reporter mice. These studies will shed new light on molecules and mechanisms shared during development of sensory systems and lead to further insights into the molecular and cellular biology of olfactory perception, particularly the recovery of olfactory function following injury.Project Narrative: This project will shed light on the function of a complex glycan that is required for development of the olfactory system. In addition, as a model for spontaneous regeneration, these studies are likely to broaden our understanding of potential treatments for peripheral nerve injury and neurodegenerative disease.