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（由申请人提供）：虽然神经发生主要发生在发育过程中，但它是一个持续一生的活跃过程，并且可能在正常学习和记忆中发挥作用。随着年龄的增长，神经发生水平会降低，可能在阿尔茨海默病 (AD) 等神经退行性疾病中也会发生这种情况。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。使用一种新的药物发现范式来选择治疗神经退行性疾病的候选药物，该范式基于多种与年龄相关的病理的细胞培养模型的功效。该计划鉴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 小鼠的认知丧失。 J147 在小鼠、培养的成年大鼠海马前体细胞以及人 ESC 衍生的神经前体细胞中也具有神经源性。此外，它还具有抑制星形胶质细胞分裂的独特能力。本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，并利用该化合物更好地了解体内和细胞培养模型中参与神经发生的分子途径。因此，响应 J147 产生的神经样细胞的表型将在动物和可产生神经或神经胶质细胞的大鼠海马前体细胞系中得到表征。由于 J147 等化合物在 AD 中具有治疗潜力，人们会问 J147 是否可以在其他神经源性化合物无法发挥作用的高龄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减少，并且将询问J147是否仍然能够增强记忆。最后，一种新的蛋白质组学方法将用于识别负责 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 J147 的治疗应用基于操纵神经干细胞以改善中枢神经系统健康。