Molecular mechanisms regulating mitral cell development

调节二尖瓣细胞发育的分子机制

• 批准号: 8274696
• 负责人: Fumiaki Imamura
• 金额: $ 6.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274696
• 关键词: Address; Afferent Neurons; Anosmia; Apoptosis; Asperger Syndrome; Axon; Brain; Brain region; Bromodeoxyuridine; Calculi; Cell Differentiation process; Cells; Child; Cytoplasmic Granules; Data; Dendrites; Development; Electroporation; Embryo; Embryonic Development; Event; Exhibits; Extracellular Matrix; Functional disorder; Generations; Goals; Growth; Injection of therapeutic agent; Interneurons; Kallmann Syndrome; Knockout Mice; Label; Location; Methods; Molecular; Morphology; Neuraxis; Neurons; Olfactory Cortex; Pathway interactions; Patients; Pattern; Plasmids; RNA Interference; Research; Role; Smell Perception; Specificity; Staging; Synapses; Synaptic Vesicles; Testing; TimeLine; Work; cell type; developmental disease; hyposmia; in utero; information processing; insight; knock-down; molecular marker; molecular phenotype; neuron development; neuronal cell body; neuronal circuitry; novel; olfactory bulb; postnatal; precursor cell; public health relevance; synaptogenesis; transcription factor

DESCRIPTION (provided by applicant): The olfactory bulb (OB) is the first relay station of olfactory information in the central nervous system (CNS). The general laminar organization and elaborate morphologies of OB projection neurons, mitral/tufted cells, have been well known for several decades, but we continue to lack insight into their developmental mechanisms. Previous studies revealed the timeline of anatomical changes of developing mitral cells. The next step is to understand the molecular determinants and pathways regulating the specific anatomical changes occurring during mitral/tufted cell development, which is the long-term goal of this project. To accomplish this goal, I have established a novel method to manipulate molecular expression in subsets of developing mitral cells. Using this method, this proposal seeks to investigate the roles of several candidate molecules in mitral cell development. The candidate molecules are three transcription factors (Tbr1, Tbr2, Tbx21), an extracellular matrix molecule (Reelin), a transmembrane protein (Protocadherin21), and a synaptic vesicle protein (vGluT1). All of these candidate molecules have been selected because they are specifically expressed by mitral/tufted cells in developing OB. In Aim 1, the temporal expression pattern of candidate molecules in developing mitral cells will be established. In Aim 2, the fate of mitral cell precursors in the absence of Tbr1 or Tbr2 will be determined. In Aim 3, I will test hypotheses regarding the roles of Tbx21, Reelin, Protocadherin21, and vGluT1 in morphological development and/or synapse formation of mitral cells. These studies will provide us with new significant insights into molecular determinants and pathways working in developing mitral cells, which can then serve as a stepping stone to further research. I believe that this will become one of the leading works for neuronal circuitry formation during development of both the OB and elsewhere in the CNS where these molecules are expressed. PUBLIC HEALTH RELEVANCE: Olfactory information is transmitted to diverse brain regions through mitral/tufted cells in the olfactory bulb. Several developmental disorders also have olfactory dysfunctions: for example, many Asperger's syndrome children have hyperosima (increased ability to smell) or hyposmia (reduced ability to smell); and Kallmann syndrome patients have anosmia (inability to smell). The general goal of this project is to understand the developmental mechanisms of mitral/tufted cells which could help in finding a cure of these olfactory dysfunctions.

描述（由申请人提供）：嗅球（OB）是中枢神经系统（CNS）中嗅觉信息的第一个中继站。 OB 投射神经元、二尖瓣/簇状细胞的一般层状组织和复杂形态已经众所周知几十年了，但我们仍然缺乏对其发育机制的深入了解。先前的研究揭示了发育中的二尖瓣细胞的解剖变化的时间表。下一步是了解调节二尖瓣/簇状细胞发育过程中发生的特定解剖变化的分子决定因素和途径，这是该项目的长期目标。为了实现这一目标，我建立了一种新方法来操纵发育中的二尖瓣细胞亚群的分子表达。该提案旨在利用这种方法研究几种候选分子在二尖瓣细胞发育中的作用。候选分子是三种转录因子（Tbr1、Tbr2、Tbx21）、细胞外基质分子（Reelin）、跨膜蛋白（Protocadherin21）和突触小泡蛋白（vGluT1）。选择所有这些候选分子是因为它们在发育中的 OB 中由二尖瓣/簇状细胞特异性表达。在目标 1 中，将建立候选分子在发育中的二尖瓣细胞中的时间表达模式。在目标 2 中，将确定在 Tbr1 或 Tbr2 缺失的情况下二尖瓣细胞前体细胞的命运。在目标 3 中，我将测试有关 Tbx21、Reelin、Protocadherin21 和 vGluT1 在二尖瓣细胞形态发育和/或突触形成中的作用的假设。这些研究将为我们提供有关二尖瓣细胞发育的分子决定因素和途径的新的重要见解，从而可以作为进一步研究的垫脚石。我相信这将成为 OB 和 CNS 中表达这些分子的其他部位发育过程中神经元回路形成的主要工作之一。 公共卫生相关性：嗅觉信息通过嗅球中的二尖瓣/簇状细胞传输到不同的大脑区域。一些发育障碍也有嗅觉功能障碍：例如，许多阿斯伯格综合症儿童患有嗅觉亢进（嗅觉能力增强）或嗅觉减退（嗅觉能力降低）；卡尔曼综合征患者患有嗅觉丧失症（无法嗅觉）。该项目的总体目标是了解二尖瓣/簇状细胞的发育机制，这有助于找到治疗这些嗅觉功能障碍的方法。