ASTROCYTE-RELATED MOLECULAR MECHANISMS UNDERLYING ALTERED NEURONAL PLASTICITY IN

星形胶质细胞相关的神经元可塑性改变的分子机制

• 批准号: 8440519
• 负责人: JORGE A BUSCIGLIO
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440519
• 关键词: ASTROCYTE; RELATED; MOLECULAR; MECHANISMS; UNDERLYING

Project 2: Astrocyte-related molecular mechanisms underlying altered neuronal plasticitv in Down syndrome The goal of this project is to understand the molecular mechanisms associated with abnormal astrocyte function and their role in altered structural and functional plasficity in the Down's syndrome (DS) brain. Astrocytes are critical regulators of neuronal stem cells (NSCs) proliferation and differentiafion as well as dendritic spine development and synaptogenesis. We found metabolic deficits in DS astrocytes directly associated with reduced NSCs viability and aberrant spine formation. To investigate the molecular pathways associated with abnormal astrocyte function and its role in DS altered structural and functional neuroplasticity we propose: 1. To identify the molecular alterations in OS astrocytes responsible for impaired NSCs neurogenesis and spine pathology. We will define the role of intracellular AU and mitochondrial dysfunction in astrocyte secretory deficits, and the role of reduced APPs and thrombospondin 1 (TSP-1) secrefion in NSCs and spine pathology. 2. To analyze the effectiveness of mitochondrial cofactors and B-secretase inhibitors to prevent or revert DS astrocyte secretory deficits and concomitant NSCs and spine alterations. 3. A) To study the relation between astrocyte alterations, neurogenesis and spine anomalies in DS brains. We will generate normative data on the associafion between astrocyte alterations and NSCs and spine deficits in DS individuals. B) To assess the usefulness of TSP-1 levels in CSF and plasma as a biomarker of AD. We propose to perform preliminary studies to evaluate the usefulness of TSP-1 levels in plasma and CSF as a biomarker of AD in sporadic AD and DS+AD pafients. We will take advantage of our extensive experience culturing primary human nerve cells derived from fetal brain tissue. NSCs cultures in the form of neurospheres, pure astrocyte cultures, and cocultures of rat hippocampal neurons growing on top of human astrocytes (normal and DS) will be utilized for aims 1 and 2. Aim 3 will utilize post-mortem brain samples and CSF and plasma samples provided by the Neuropathology Core. The Stafistical Core will provide feedback in all statistical procedures.

项目2：唐氏综合症中神经元塑性塑料的基于的与星形胶质细胞相关的分子机制，该项目的目的是了解与异常星形胶质细胞功能相关的分子机制及其在唐氏综合症（DS）大脑中改变结构和功能性质量变化中的作用。星形胶质细胞是神经元干细胞（NSCS）增殖和分化以及树突状棘发育和突触发生的关键调节剂。我们发现DS星形胶质细胞中的代谢缺陷与NSC的生存能力和异常形成直接相关。为了研究与星形胶质细胞功能异常相关的分子途径及其在DS中的作用改变了结构和功能性神经可塑性，我们提出：1。确定导致NSC神经发生受损的OS星形胶质细胞的分子改变和棘突病理学。我们将定义细胞内AU和线粒体功能障碍在星形细胞分泌缺陷中的作用，以及减少的应用程序和血小板传播1（TSP-1）在NSC和脊柱病理学中的作用。 2。分析线粒体辅因子和B-分泌酶抑制剂的有效性，以预防或恢复DS星形胶质细胞分泌缺陷以及随之而来的NSC和脊柱改变。 3。a）研究DS大脑中星形胶质细胞改变，神经发生和脊柱异常之间的关系。我们将生成有关DS个体中星形胶质细胞改变与NSC和脊柱缺陷之间关联的规范数据。 b）评估TSP-1水平在CSF和血浆中的有用性，作为AD的生物标志物。我们建议进行初步研究，以评估TSP-1水平在血浆和CSF中作为AD在零星AD和DS+AD Pafients中的AD生物标志物的实用性。我们将利用我们的丰富经验来培养胎儿脑组织的原发性人神经细胞。 NSC培养物的形式，纯净的星形胶质细胞培养物以及生长在人类星形胶质细胞（正常和DS）之上的大鼠海马神经元的共培养物将用于目标1和2。AIM3将利用邮政脑样本以及CSF和血浆样品由Neuroplopsaly提供的邮政素。 Stafithice Core将在所有统计程序中提供反馈。