In vivo neuroprotective role of astrocyte mitochondrial metabolism during aging

星形胶质细胞线粒体代谢在衰老过程中的体内神经保护作用

• 批准号: 7907382
• 负责人: JAMES D LECHLEITER
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907382
• 关键词: Address; Affect; Age; Age-Months; Aging; Aging-Related Process; Agonist; Animal Model; Animals; Antioxidants; Astrocytes; Brain; Brain Infarction; Cell physiology; Cerebral Ischemia; Cerebrum; Consumption; Cysteine; Cytosol; Data; Dementia; Dependence; Drug Metabolic Detoxication; Dyes; Enzymes; Excision; Exhibits; Fluo 4; Gamma-glutamyl transferase; Glutamate-Cysteine Ligase; Glutathione; Goals; Human; Hydrogen Peroxide; Image; Imaging Techniques; Individual; Infarction; Inflammatory; Inflammatory Response; Knockout Mice; Label; Lasers; Lesion; Life; Ligands; Ligase; Lipid Peroxidation; Longevity; Maintenance; Measurement; Measures; Mediating; Metabolic; Metabolism; Microscopy; Mitochondria; Monitor; Mus; Neurons; Oligomycins; Oxidative Stress; Pathway interactions; Physiological; Play; Process; Production; Purinoceptor; Reporting; Research; Resistance; Role; Rose Bengal; Ruthenium; Signal Pathway; Signal Transduction; Site; Stroke; TNFRSF5 gene; Tail; Testing; Transgenic Mice; Veins; acivicin; aldehyde dehydrogenases; antibody conjugate; astrocyte mediated neuroprotection; enzyme activity; glutathione peroxidase; in vivo; inhibitor/antagonist; irradiation; middle age; monochlorobimane; neuroprotection; novel; oxidative damage; receptor; research study; response; therapeutic target; two-photon; uptake

DESCRIPTION (provided by applicant): Astrocytes play a key role in the protection and maintenance of the brain. Neuronal glutathione levels (GSH) are rapidly depleted during oxidative stress, and its re-synthesis is dependent on astrocyte GSH production. These physiological functions requires that astrocytes be capable of rapidly increasing their metabolic activity. During aging, little is known about the cumulative effects of oxidative damage on astrocytes. Degradation of their supportive and neuroprotective functions is likely to contribute to the aging process. Evidence is presented showing that astrocyte neuroprotection is diminished with age. It is also demonstrated that astrocyte resistance to oxidative stress and neuroprotection can be enhanced by activation of a purinergic receptor (P2Y-R) signaling pathway in cultured astrocytes as well as in whole animal models. This enhanced protection pathway appears to be dependent on increased mitochondrial function in astrocytes. The long-term goal of this proposal is to understand the role of astrocytes in the maintenance and protection of the brain during aging. The overall hypothesis is that neuroprotection can be enhanced by increasing mitochondrial metabolism in astrocytes at anytime during the aging process. The following Specific Aims are proposed to test this hypothesis. 1) To determine the mechanism by which purinergic receptor (P2Y-R) activation in astrocytes increases neuroprotection in the living mouse cortex throughout aging. 2) To define the impact of mitochondrial ROS damage on P2Y-R mediated astrocyte neuroprotection during the aging process in vivo. 3) To non-invasively delineate the receptor dependence of Ca2+ stimulated mitochondrial metabolism in astrocytes for in vivo neuroprotection during aging. Young, middle-aged and old mice as well from animal models with dysfunctional mitochondria and altered antioxidant enzyme activity will be used to carry out these aims. Single and mutliphoton microscopy will be used to image changes in mitochondrial and cellular function in vivo. Small animal fluorescent imaging will be used to monitor the progression of focal cerebral infarcts (strokes) in living mice brains. These studies are important to understand the underlying mechanisms of aging in humans. The identification and characterization of a novel protective pathway in the brain, which can be activated throughout the aging process, will also serve as an attractive therapeutic target to address many neuropathological processes.Accumulation of oxidative damage to astrocytes is likely to degrade their supportive and neuroprotective functions and significantly contribute to the aging process. Data collected from this research will help to identify and characterize novel protective pathways in astrocytes that can be activated to protect the brain during aging. These pathways should also serve as an attractive therapeutic targets to address many neuropathological processes, including stroke and dementias.

描述（由申请人提供）：星形胶质细胞在保护和维护大脑中起关键作用。神经元谷胱甘肽水平（GSH）在氧化应激期间迅速耗尽，其重新合成取决于星形胶质细胞GSH的产生。这些生理功能要求星形胶质细胞能够快速增加其代谢活性。在衰老过程中，氧化损伤对星形胶质细胞的累积影响知之甚少。其支持性和神经保护功能的退化可能会导致衰老过程。有证据表明，星形胶质细胞神经保护因年龄而减少。还证明，通过激活培养的星形胶质细胞以及整个动物模型中的嘌呤能受体（P2Y-R）信号通路，可以通过激活嘌呤能受体（P2Y-R）信号通路来增强星形胶质细胞对氧化应激和神经保护性的抗性。这种增强的保护途径似乎取决于星形胶质细胞中线粒体功能的增加。该提案的长期目标是了解星形胶质细胞在老化过程中的维持和保护中的作用。总体假设是，通过在老化过程中的任何时间增加线粒体代谢，可以通过增加线粒体代谢来增强神经保护作用。提出了以下特定目的来检验这一假设。 1）确定星形胶质细胞中嘌呤能受体（P2Y-R）激活的机制可增加整个衰老的活小鼠皮质中的神经保护作用。 2）在体内衰老过程中，线粒体ROS损伤对P2Y-R介导的星形胶质细胞神经保护的影响。 3）非侵入性描绘了在衰老期间体内神经保护的星形胶质细胞中Ca2+刺激的线粒体代谢的受体依赖性。年轻，中年和老鼠以及来自具有功能障碍的线粒体和抗氧化酶活性改变的动物模型将用于执行这些目标。单个和Mutliphoton显微镜将用于图像体内线粒体和细胞功能的变化。小动物荧光成像将用于监测活小鼠大脑中局灶性脑梗塞（中风）的进展。这些研究对于了解人类衰老的潜在机制很重要。可以在整个衰老过程中激活的大脑中新型保护途径的鉴定和表征也将成为解决许多神经病理学过程的有吸引力的治疗靶标。对星形胶质层的氧化损害的积累可能会降低其支持性和神经药物的功能，并显着有助于衰老过程。从这项研究中收集的数据将有助于识别和表征星形胶质细胞中的新型保护途径，这些保护途径可以在衰老过程中被激活以保护大脑。这些途径还应作为解决许多神经病理过程（包括中风和痴呆症）的有吸引力的治疗靶标。