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Characterization of a Potent Neurogenic Compound

强效神经源性化合物的表征

基本信息

批准号：
8461542
负责人：
DAVID R SCHUBERT
金额：
$ 23.16万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461542
关键词：
Adult Age Alzheimer&apos s Disease Animals Astrocytes Behavioral Biological Assay Brain Brain-Derived Neurotrophic Factor Bromodeoxyuridine Cell Culture Techniques Cell Differentiation process Cell Line Cell Proliferation Cell division Cells Commit Data Data Set Development Dominant-Negative Mutation Fluoxetine Glial Fibrillary Acidic Protein Goals Health Hippocampus (Brain)Impaired cognition In Vitro Investigation Label Laboratory Study Lead Learning Life Memory Memory impairment Methods Modeling Molecular Molecular Genetics Mus Nerve Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurons Neuroprotective Agents Neurotrophic Tyrosine Kinase Receptor Type 2 Oligodendroglia Pathology Pathway interactions Pharmaceutical Preparations Phenotype Physiologic pulse Play Premature aging syndrome Process Production Property Proteins Proteomics Radiation Rattus Rodent Role Scheme Serotonin Services Signal Pathway Staining method Stains Stem cells Subfamily lentivirinae Synapses Technology Testing Therapeutic Time Transgenic Mice Transgenic Organisms Western Blotting Work adult neurogenesis age related aged base cell type cognitive function drug candidate drug discovery human embryonic stem cell immunocytochemistry improved in vivo molecular marker nerve stem cell nestin protein neural precursor cell neurogenesis novel precursor cell prevent research study response screening senescence stem cell division therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Although neurogenesis occurs primarily during development, it is an active process that persists throughout life, and may play a role in normal learning and memory. Decreased levels of neurogenesis occur with age and perhaps in neurodegenerative conditions such as Alzheimer's disease (AD). Therefore, understanding the molecular basis of stem cell division and differentiation within the central nervous system (CNS) deserves thorough investigation. A novel drug discovery paradigm was used to select drug candidates for the treatment of neurodegenerative diseases that is based on efficacy in cell culture models of multiple, age-associated pathologies. This scheme has identified a potent, orally active compound, J147, which facilitates memory in normal rodents, prevents behavioral deficits and synaptic protein loss in AD transgenic mice, and reverses cognitive loss in aged transgenic AD mice. J147 is also neurogenic in mice, in adult rat hippocampal precursor cells in culture, and for human ESC-derived neural precursor cells. In addition, it has the unique ability of inhibiting the division of cells destined to be astrocytes. The overall aim in this study is to identify the type and fate of cells that respond to J147 in the mouse brain and to use this compound to better understand the molecular pathways involved in neurogenesis both in vivo and in cell culture models. Therefore the phenotype of the nerve-like cells made in response to J147 will be characterized both in animals and in a rat hippocampal precursor cell line that can produce either nerve or glia. Because the therapeutic potential of compounds like J147 in AD, it will be asked if J147 can induce neurogenesis in very old mice where other neurogenic compounds fail to act. Importantly, neurogenesis will be reduced by two independent methods and it will be asked if J147 is still able to enhance memory. Finally, a new proteomics approach will be used to identify the molecular signaling pathways responsible for J147-induced cell division and nerve differentiation. Results from this study may lead to a therapeutic application of J147 based upon manipulating neural stem cells to improve CNS health.

描述(申请人提供)：虽然神经发生主要发生在发育过程中，但它是一个活跃的过程，持续整个生命，并可能在正常的学习和记忆中发挥作用。神经发生水平随着年龄的增长而降低，可能在阿尔茨海默病(AD)等神经退行性疾病中也会发生。因此，了解中枢神经系统(CNS)内干细胞分裂和分化的分子基础值得深入研究。一种新的药物发现范式被用于选择治疗神经退行性疾病的候选药物，该方法基于多种年龄相关病理的细胞培养模型的疗效。该方案已经确定了一种有效的口服活性化合物J147，它可以促进正常啮齿动物的记忆，防止AD转基因小鼠的行为缺陷和突触蛋白丢失，并逆转老年转基因AD小鼠的认知损失。J147在小鼠、培养中的成年大鼠海马神经前体细胞和人胚胎干细胞来源的神经前体细胞中也是神经源性的。此外，它还具有独特的能力，可以抑制注定成为星形胶质细胞的细胞的分裂。这项研究的总体目标是确定小鼠大脑中对J147做出反应的细胞的类型和命运，并使用这种化合物更好地了解体内和细胞培养模型中涉及神经发生的分子途径。因此，对J147的反应所产生的神经样细胞的表型将在动物和能够产生神经或神经胶质的大鼠海马体前体细胞系中得到表征。由于像J147这样的化合物在阿尔茨海默病中的治疗潜力，人们会问J147是否可以在其他神经原化合物无法作用的非常老的小鼠中诱导神经再生。重要的是，神经发生将通过两种独立的方法减少，人们将询问J147是否仍然能够增强记忆。最后，将使用一种新的蛋白质组学方法来确定J147诱导细胞分裂和神经分化的分子信号通路。这项研究的结果可能导致J147在操纵神经干细胞以改善中枢神经系统健康的基础上的治疗应用。