Characterization of Neural Stem Cells in the Adult Brain

成人大脑中神经干细胞的表征

• 批准号: 8281560
• 负责人: Arturo Alvarez-Buylla
• 金额: $ 54.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281560
• 关键词: Abbreviations; Address; Adenoviruses; Adult; Age; Animal Model; Anterior; Antimitotic Agents; Apical; Architecture; Aspartate; Astrocytes; B Cell Proliferation; B-Lymphocytes; Birth; Brain; Bromodeoxyuridine; Cell Cycle; Cell Proliferation; Cell division; Cell physiology; Cells; Chain Migrations; Cilia; Clinic; Cytosine; Data; Detection; Development; Electron Microscope; Embryo; Ependymal Cell; Epithelial; Erinaceidae; Figs - dietary; Fluorescence-Activated Cell Sorting; Funding; GLAST Protein; Galactosylceramides; Generations; Genetic; Glial Fibrillary Acidic Protein; Glutamates; Growth Factor Receptors; Health; Hippocampus (Brain); Horns; Human; Human Development; Human Resources; Immunohistochemistry; In Situ Hybridization; In Vitro; Interneurons; Knowledge; Label; Laboratories; Lateral; Lead; Length; Life; Liquid substance; Location; Maintenance; Medial; Methods; Mus; Myelin Basic Proteins; Natural regeneration; Neonatal; Neural Cell Adhesion Molecules; Neuroglia; Neurons; Nuclear Antigens; Nuclear Pore Complex; Oligodendroglia; Organelles; Pathway interactions; Pattern; Phenotype; Physiologic pulse; Platelet-Derived Growth Factor; Play; Polymerase Chain Reaction; Progress Reports; Property; Proteins; Radial; Reagent; Receptor Signaling; Regulation; Reporting; Research; Research Design; Research Methodology; Rodent; Role; Route; Signal Transduction; Signaling Molecule; Sonic hedgehog protein; Source; Staging; Stem cells; Steroids; Stream; Structure; Structure of thyroid parafollicular cell; Subependymal; Therapeutic; Therapeutic Uses; Time; Translating; Translations; Tubulin; Tyrosine 3-Monooxygenase; Ventricular; Work; adult neurogenesis; age related; base; brain repair; calbindin; calretinin; cell type; galactocerebroside; granule cell; human SMO protein; immunocytochemistry; in vivo; lateral ventricle; migration; nerve stem cell; nestin protein; neuroblast; neurogenesis; neuronal cell body; novel strategies; nucleoside analog; olfactory bulb; polysialyl neural cell adhesion molecule; postnatal; postnatal human; progenitor; promoter; research study; self-renewal; subventricular zone; transcription factor; tumor

DESCRIPTION (provided by applicant): Neurogenesis continues in the adult brain within an extensive germinal zone on the walls of the lateral ventricles called the Subventricular Zone (SVZ). SVZ astrocytes (B cells) function as adult neural stem cells (NSCs), generating transit amplifying C cells which give rise to neurons (Type A cells). New SVZ neurons migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) where they differentiate into multiple types of local interneurons. It remains unknown if B cells self-renew in vivo, how many times C cells divide before they generate new neurons, and whether generation of different neuronal lineages involves different patterns of proliferation for B and C cells. Aim 1 will address these important gaps in our understanding of the SVZ. A recent study has redefined the architecture for the SVZ, revealing a pinwheel arrangement of B and ependymal cells and the apical-basal organization of B cells. The core of these pinwheels contains the apical compartments of B cells with primary cilia contacting the ventricle. Primary cilia concentrate essential components for Shh signal transduction and other pathways known to regulate B cell proliferation. Aim 2 will explore the role of primary cilia in adult SVZ NSCs. SVZ astrocytes with NSC properties in vitro have also been identified in adult human brain, suggesting that SVZ adult NSCs could be used for therapeutic neuronal and glial replacement. However, the structure of the human SVZ is different from that in rodents. In addition, the extent of SVZ NSC proliferation in vivo and the ability of these cells to generate neurons that migrate long distances into the OB in adult humans remains highly controversial. This controversy is addressed by work proposed in Aim 3. Experiments in Aim 1 will investigate the cell cycle times of different SVZ progenitors, determine whether B cells self-renew in vivo and the number of times C cells divide before generation of different types of neurons in the rodent SVZ. Aim 2 uses genetic methods to remove the primary cilia in adult rodent NSCs to investigate the role of this apical organelle in the proliferation of adult NSCs. Aim 3 will determine the developmental origins of the unique organization of the adult human SVZ and will investigate age dependent changes in the levels of SVZ proliferation and possible fates of young neurons derived from the SVZ. We also intend to clarify whether an RMS exists in adult human brain and how this structure changes through development. Preliminary results suggest that: 1) B cells are consumed with age and their proliferation may be regionally regulated; 2) primary cilia play a key role in the proliferation of adult NSCs; 3) young neurons are present in the developing human SVZ, but interestingly very scarce along the olfactory track; 4) a possible medial extension of the human RMS may exist. The above experiments will provide basic information on the most extensive germinal niche in the postnatal brain. PUBLIC HEALTH RELEVANCE: Neural Stem Cells (NSCs) that continually generate new neurons exist in the walls of the liquid filled cavities (ventricles) in the adult brain. This germinal region, called the subventricular zone (SVZ), is the largest single source of NSCs in the adult brain. In rodents, new neurons born in the SVZ migrate to the olfactory bulb, where they continually replace older neurons. The progenitor cells involved in adult neurogenesis in rodents have been identified, but we do not know how frequently they divide or the precise pattern of cell divisions and cell cycle length that leads to the generation of different types of neurons. Experiments proposed here will specifically determine the cell cycle time for adult SVZ progenitors and determine if cell cycle dynamics vary for different regions of the SVZ. The regulation of SVZ NSCs proliferation remains poorly understood. Recent work indicates that the NSCs contact the ventricle directly with a specialized extension called the primary cilium. Primary cilia are like cellular antennas that are receptive to external signals and multiple important growth factor receptors and signaling molecules are thought to be concentrated in primary cilia. We propose experiments to remove the primary cilium in adult NSCs and study the effects on the proliferation of adult NSCs. It remains controversial whether neurogenesis and long-range migration to the olfactory bulb, like those observed in adult rodents, occurs in adult humans. We propose to study how the SVZ develops in humans and to identify migratory routes and levels of proliferation at different ages. This information is essential to translate some of our observations in animal models to the clinic. This work will help in the development of novel strategies for brain repair and suggest how derailed proliferation of endogenous precursors might lead to tumor formation.

描述（由申请人提供）：在成年大脑中，神经发生在侧心壁的广泛生发区内继续，称为室室下区（SVZ）。 SVZ星形胶质细胞（B细胞）起着成年神经干细胞（NSC）的作用，产生了引起神经元（A型细胞）的Transit扩增C细胞。新的SVZ神经元通过延髓迁移流（RMS）迁移到嗅球（OB），在那里它们分化为多种类型的局部神经元。 B细胞是否在体内自我更新，C细胞在产生新神经元之前分裂了多少次，以及不同神经元谱系的产生是否涉及B和C细胞增殖的不同模式。 AIM 1将在我们对SVZ的理解中解决这些重要差距。最近的一项研究重新定义了SVZ的架构，揭示了B和dend依室细胞的链球定位以及B细胞的顶碱组织。这些风车的核心包含B细胞的顶室，主要纤毛接触心室。用于SHH信号转导和其他已知可以调节B细胞增殖的途径的原发性纤毛浓缩材料。 AIM 2将探索原发性纤毛在成人SVZ NSC中的作用。在成年人大脑中也发现了具有NSC特性的SVZ星形胶质细胞，这表明SVZ成人NSC可用于治疗性神经元和神经胶质替代。但是，人类SVZ的结构与啮齿动物中的结构不同。此外，体内SVZ NSC增殖的程度以及这些细胞产生长距离迁移到成人人类中OB的神经元的能力仍然存在很大争议。 AIM 3中提出的工作解决了这一争议。AIM1中的实验将研究不同SVZ祖细胞的细胞周期时间，确定B细胞在体内自我更新以及C细胞在啮齿动物SVZ中产生不同类型的神经元之前的次数C细胞的数量。 AIM 2使用遗传方法去除成年啮齿动物NSC中的原发性纤毛，以研究该顶端细胞器在成年NSC增殖中的作用。 AIM 3将确定成人人类SVZ独特组织的发展起源，并将研究SVZ增殖水平的年龄依赖性变化以及来自SVZ的年轻神经元的可能命运。我们还打算澄清RMS是否存在于成年人大脑中，以及这种结构如何通过发展而变化。初步结果表明：1）B细胞随着年龄的增长而消耗，其增殖可能受到区域调节； 2）原发性纤毛在成人NSC的扩散中起关键作用； 3）年轻的神经元存在于发展中的人类SVZ中，但有趣的是沿嗅觉曲目非常稀缺； 4）可能存在人RMS的内侧扩展。以上实验将提供有关产后大脑中最广泛的生发生态位的基本信息。 公共卫生相关性：成年大脑中液体充满腔（心室）的壁中存在不断产生新神经元的神经干细胞（NSC）。该生发区域称为室内区（SVZ），是成人大脑中最大的NSC源。在啮齿动物中，出生在SVZ中的新神经元迁移到嗅球，在那里它们不断取代较老的神经元。已经鉴定出参与啮齿动物中成年神经发生的祖细胞，但我们不知道它们的频率或细胞分裂的精确模式和细胞周期长度的精确模式，从而导致不同类型的神经元的产生。此处提出的实验将明确确定成年SVZ祖细胞的细胞周期时间，并确定SVZ不同区域的细胞周期动力学是否有所不同。 SVZ NSC增殖的调节仍然鲜为人知。最近的工作表明，NSC与称为原发性纤毛的专门扩展直接接触心室。原发性纤毛就像可以接受外部信号的细胞天线，而多个重要的生长因子受体和信号分子被认为集中在原发性纤毛中。我们提出了实验，以去除成人NSC中的主要纤毛，并研究对成年NSC增殖的影响。是否存在神经发生和远距离迁移到嗅球，就像在成年啮齿动物中所观察到的那样，这仍然是有争议的。我们建议研究SVZ如何在人类中发展，并确定不同年龄段的迁移途径和增殖水平。这些信息对于将我们在动物模型中的某些观察结果转换为诊所至关重要。这项工作将有助于开发新的脑修复策略，并暗示内源性前体的增殖如何导致肿瘤形成。