Characterization of a Potent Neurogenic Compound

强效神经源性化合物的表征

• 批准号: 8374346
• 负责人: DAVID R SCHUBERT
• 金额: $ 28.8万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 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/8374346
• 关键词: Adult; Age; Alzheimer' 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; Screening procedure; 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; senescence; stem cell division; therapeutic target; uptake

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. PUBLIC HEALTH RELEVANCE: It is now generally recognized that new nerve cells continue to be produced in the adult brain, but there are currently very few ways to stimulate that process. We have recently made a very potent compound that can stimulate the production of new neurons in both young and old mice. The goal of this project is to better characterize the types of nerve cells that this compound generates and determine how it works.

描述（由申请人提供）：尽管神经发生主要发生在开发过程中，但它是一个活跃的过程，它始终存在，并且可能在正常的学习和记忆中发挥作用。神经发生水平降低随着年龄的增长，也许是在阿尔茨海默氏病（AD）等神经退行性疾病中发生的。因此，理解干细胞分裂的分子基础和中枢神经系统（CNS）内的分化值得彻底的研究。一种新型的药物发现范式用于选择候选药物来治疗基于多种，年龄相关病理学的细胞培养模型的神经退行性疾病。该方案已经鉴定出有效的口腔活性化合物J147，该化合物促进了正常啮齿动物的记忆，可防止AD转基因小鼠的行为缺陷和突触蛋白损失，并逆转老年转基因AD小鼠的认知损失。 J147在培养物中的小鼠，成年大鼠海马前体细胞和人ESC衍生的神经前体细胞中也是神经源。此外，它具有抑制注定为星形胶质细胞的细胞分裂的独特能力。这项研究的总体目的是确定对小鼠大脑中对J147反应的细胞的类型和命运，并使用该化合物更好地了解在体内和细胞培养模型中涉及神经发生的分子途径。因此，在动物和大鼠海马前体细胞系中，对响应J147产生的神经样细胞的表型将被表征，该细胞可以产生神经或神经胶质。由于AD中J147等化合物的治疗潜力，因此将询问J147是否可以在其他神经源性化合物无法作用的非常古老的小鼠中诱导神经发生。重要的是，神经发生将通过两种独立的方法降低，并且将询问J147是否仍然能够增强记忆力。最后，将使用一种新的蛋白质组学方法来识别负责J147诱导的细胞分裂和神经分化的分子信号传导途径。这项研究的结果可能会导致基于操纵神经干细胞改善CNS健康的J147的治疗应用。 公共卫生相关性：现在普遍认识到，成人大脑中继续产生新的神经细胞，但是目前很少有刺激该过程的方法。最近，我们制作了一种非常有效的化合物，可以刺激年轻小鼠和老鼠的新神经元的产生。该项目的目的是更好地表征该化合物生成的神经细胞的类型并确定其工作原理。