Metabolic requirements of adult neural stem cells

成体神经干细胞的代谢需求

基本信息

批准号：
8321500
负责人：
Philip J Horner
金额：
$ 15.84万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321500
关键词：
Accounting Adult Aerobic Affect Aging Amino Acids Antibodies Antimitotic Agents Area Behavior Biology Body Weight Brain Carbohydrates Cell Proliferation Cell Respiration Cell division Cells Consumption Control Animal Coupled Data Dependence Dependency Development Diet Disease Energy-Generating Resources Exercise Fatty Acids Fatty acid glycerol esters Genomics Glucose Glycogen Goals Hippocampus (Brain)Impaired cognition In Vitro Intrinsic factor Ketone Bodies Ketones Label Lead Life Link Longevity Malignant Neoplasms Measures Metabolic Metabolism Methods Milk Mitochondria Mitosis Mitotic Mitotic Activity Molecular Mothers Mus Mutation Natural regeneration Nerve Degeneration Neuraxis Neurons Oxidative Stress Oxygen Consumption Pharmacological Treatment Physiological Polyunsaturated Fatty Acids Pregnancy Production Prosencephalon Public Health Reactive Oxygen Species Research Design Resources Respiration Running Slice Source Staining method Stains Stem cells System Testing Thymidine Time Tissues Undifferentiated adult neurogenesis age related aged aging brain analog base cost dentate gyrus dosage fatty acid metabolism fatty acid oxidation in vivo inhibitor/antagonist lateral ventricle meetings nerve stem cell neurogenesis normal aging novel oxidation progenitor regenerative relating to nervous system research study respiratory stem subventricular zone tissue processing young adult

项目摘要

DESCRIPTION (provided by applicant): Although neural stem cells give rise to new neurons in several regions of the adult mammalian brain, rates of neurogenesis do not remain constant. Aging leads to decreased neuron production, while voluntary exercise and high-fat diet have been shown to increase rates of adult neurogenesis. We propose changes in availability of metabolic fuels as a common mechanism underlying these phenomena. Using a flow culture chamber fitted to measure multiple real-time respiratory endpoints, we have shown that both young and aged neural stem cells have extraordinarily high rates of oxidative metabolism and do not require glucose to sustain oxygen consumption. These results suggest that neural stem cells are dependent upon some novel endogenous fuel to maintain high levels of aerobic respiration necessary for cellular division. We hypothesize that adult neural stem cells are dependent upon metabolism of fatty acids or ketone bodies for metabolic and mitotic activity. During development, the brain is dependent upon polyunsaturated fatty acids and ketone bodies derived from mothers' milk; metabolic dependence upon these fuels may be a conserved energetic profile in neural stem cells across the lifespan, by which B-oxidation provides large quantities of ATP necessary for cellular division. We also hypothesize that high metabolic demand met by fewer mitochondria in aged neural stem cells leads to increased levels of reactive oxygen species and a higher occurrence of mitochondrial mutations. We propose identifying the fuel resources of neural stem cells, determining the metabolic costs of cellular division, and investigating whether fuel availability affects rates of neurogenesis in vivo. Manipulating the fuels available to neural stem cells in vitro and in vivo may uncover a novel mechanism by which organismal behavior, energy consumption, and cellular activity are coupled in the adult mammalian brain. We hope to impact public health by identifying mechanisms underlying behavior-induced changes in cellular activity, especially in cells capable of regeneration within the adult and aging brain.

描述（由申请人提供）：尽管神经干细胞在成年哺乳动物大脑的几个区域产生了新的神经元，但神经发生率并不能保持恒定。衰老会导致神经元的产生降低，而自愿运动和高脂饮食已显示出增加成人神经发生率。我们提出了代谢燃料的可用性变化，作为这些现象的共同机制。使用拟合的流培养室来测量多个实时呼吸终点，我们表明，年轻和老化的神经干细胞都具有极高的氧化代谢速率，并且不需要葡萄糖来维持氧气消耗。这些结果表明，神经干细胞取决于一些新型的内源性燃料，以维持细胞分裂所需的高水平有氧呼吸。我们假设成年神经干细胞取决于脂肪酸或酮体的代谢，用于代谢和有丝分裂活性。在发育过程中，大脑取决于源自母牛奶的多不饱和脂肪酸和酮体。对这些燃料的代谢依赖性可能是整个生命周期中神经干细胞中保守的能量特征，通过该燃料，B氧化提供了大量的细胞分裂ATP。我们还假设，老年神经干细胞中线粒体较少的高代谢需求会导致活性氧水平增加，线粒体突变的发生率更高。我们建议确定神经干细胞的燃料资源，确定细胞分裂的代谢成本，并研究燃料的可用性是否会影响体内神经发生率。在体外和体内操纵可用于神经干细胞的燃料可能会发现一种新的机制，通过这种机制，在成年哺乳动物大脑中，有机行为，能量消耗和细胞活性偶联。我们希望通过确定行为引起的细胞活性变化的基础机制来影响公共卫生，尤其是在成人和衰老大脑内能够再生的细胞中。