BDNF over-expression and olfactory neurogenesis

BDNF 过度表达和嗅觉神经发生

基本信息

批准号：
8431947
负责人：
KATHLEEN M GUTHRIE
金额：
$ 42.91万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-13 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431947
关键词：
Adult Apoptosis Brain Brain-Derived Neurotrophic Factor Breeding Bromodeoxyuridine Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cell Survival Cells Confocal Microscopy Cytoplasmic Granules Dendrites Detection Development Disease Fostering Goals Growth Huntington Disease Immunoprecipitation Injection of therapeutic agent Injury Interneurons Label Life Ligands Mediating Messenger RNA Monitor Morphogenesis Morphology Mus Nerve Degeneration Nerve Growth Factor Receptors Neurons Output Paracrine Communication Pathology Phase Population Process Proliferating Prosencephalon Proteins Retroviral Vector Role Sensory Deprivation Signal Transduction Stem cells Stream Structure Survival Rate Synapses Synaptic plasticity System Testing Therapeutic Transgenic Mice Vertebral column Western Blotting Wild Type Mouse Work autocrine base design granule cell human Huntingtin protein in vivo mouse model mutant nerve stem cell nervous system disorder neuroblast neurogenesis neurotrophic factor olfactory bulb progenitor promoter red fluorescent protein relating to nervous system sensory system subventricular zone synaptogenesis tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Finding ways to preserve or replace brain neurons that are vulnerable to disease or injury remains an important therapeutic goal. The mammalian olfactory bulb is the only brain structure identified to date that is known to regularly replace neurons in adulthood. Proliferating neural stem cells in the forebrain subventricular zone (SVZ) give rise to thousands of neuroblasts daily that migrate in the rostral migratory stream to the olfactory bulb and differentiate as inhibitory interneurons. The vast majority of new neurons develop as granule cells, and these modulate the activity of excitatory output neurons, the mitral cells, through synapses that form on their dendritic processes. Pre-existing granule cells gradually die, and their replacement by adult-born granule cells maintains the overall integrity of olfactory bulb circuitry, and the functional capabilities of this sensory system. About half of new granule cells die over the first few weeks of their development in the bulb, with only a fraction o the population surviving long- term. How this cell turnover is controlled within the bulb, what determines which neurons, and how many, will live or die, and how new neurons form synapses within pre-established circuits is not well understood. Much more is known is about how these processes are controlled during early development, and there may be similarities in the mechanisms involved. Trophic factor signaling is one such mechanism that operates to sculpt the sizes of neuronal populations and their connections during brain development, and continues to maintain neuron morphology and synaptic plasticity in adults. Using transgenic mice, the work described in this proposal will first determine if increasing endogenous trophic factor signaling in the bulb promotes greater survival of new granule cells under normal conditions. Secondly, granule cell survival is reduced by suppressing neural activity and by pathology associated with Huntington's disease, and trophic factor over-expression will be tested for its ability to rescue new neurons under these adverse conditions. Finally, the morphological development of new cells will be monitored to determine whether increased trophic signaling can foster their functional integration by enhancing dendrite growth and synapse formation. Identifying factors in the adult CNS that promote the survival and development of SVZ-derived progenitors under normal, as well as pathological conditions, will have important implications for adapting adult neural stem cells for therapeutic purposes. PUBLIC HEALTH RELEVANCE: In adult brain, only the olfactory system has the capacity to regularly replace older neurons with new neurons generated from SVZ stem cells. Understanding the mechanisms that control this process and favor the survival and integration of new neurons has practical implications for the design of cell-based therapeutic strategies aimed at treating neurological disorders. PUBLIC HEALTH RELEVANCE: The olfactory forebrain contains the only population of neurons that are regularly replaced by new neurons born in the adult brain. The mutation that causes Huntington's disease (HD), and conditions that reduce neural activity, inhibit the survival of new neurons in this system. This research project will test if neurotrophic factor signaling regulates the normal neuron replacement process, and if increasing trophic factor availability rescues adult-born neurons from death caused by HD pathology or suppressed network activity.

描述（由申请人提供）：寻找易于疾病或受伤的脑神经元的方法仍然是一个重要的治疗目标。哺乳动物嗅球是迄今为止唯一确定的大脑结构，该结构已知在成年期会定期替代神经元。前脑室中室里（SVZ）中增殖的神经干细胞每天会产生数千个神经细胞，这些神经细胞每天迁移到鼻迁移流到嗅球，并以抑制性神经元的形式区分。绝大多数新神经元随着颗粒细胞的形式发展，这些神经元通过在树突过程中形成的突触来调节兴奋性输出神经元（二尖瓣）细胞的活性。预先存在的颗粒细胞逐渐死亡，其替代成人颗粒细胞维持了整体完整性嗅球电路以及该感觉系统的功能功能。大约一半的新颗粒细胞在灯泡开发的前几周死亡，只有长期存活的人口只有一小部分。该细胞周转方式如何在灯泡中控制，什么决定了哪些神经元，生命或死亡的是什么，以及如何在预先建立的电路中形成突触的新神经元。众所周知，关于这些过程在早期开发过程中如何控制这些过程，涉及的机制可能存在相似之处。营养因子信号传导是一种这种机制，可在大脑发育过程中雕刻神经元种群的大小及其连接的大小，并继续保持成人的神经元形态和突触可塑性。使用转基因小鼠，该提案中描述的工作将首先确定灯泡中内源性营养因子信号是否增加会在正常条件下促进新颗粒细胞的更大生存。其次，通过抑制神经活动和与亨廷顿氏病有关的病理来降低颗粒细胞的存活，而营养因子过表达将因其在这些不良条件下营救新神经元的能力而进行测试。最后，将监测新细胞的形态发展，以确定增加的营养信号是否可以通过增强树突生长和突触形成来促进其功能整合。在正常情况下以及病理条件下，促进SVZ衍生祖细胞生存和发展的成年中枢神经系统中的因素将对适应成年神经干细胞的治疗目的具有重要意义。公共卫生相关性：在成人大脑中，只有嗅觉系统才能用SVZ干细胞产生的新神经元定期替代老年神经元。了解控制这一过程并有利于新神经元的生存和整合的机制对旨在治疗神经系统疾病的基于细胞的治疗策略的设计具有实际意义。公共卫生相关性：嗅觉前脑包含唯一的神经元群体，这些神经元经常被成人大脑中出生的新神经元所取代。引起亨廷顿氏病（HD）的突变以及减少神经活动的疾病，抑制了该系统中新神经元的存活。该研究项目将测试神经营养因子信号传导是否调节正常的神经元置换过程，以及增加的营养因子的可用性是否会使成人出生的神经元免于由HD病理导致的死亡或抑制网络活动。