Regulation of Forebrain Neurogenesis by the Energy Sensor AMP Kinase

能量传感器 AMP 激酶对前脑神经发生的调节

基本信息

批准号：
8468224
负责人：
Biplab Dasgupta
金额：
$ 32.25万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468224
关键词：
5&apos -AMP-activated protein kinase Apoptosis Area Basal Ganglia Bioenergetics Brain Bromodeoxyuridine Catabolism Cell Cycle Cell Cycle Kinetics Cell division Cells Cellular Structures Cellular biology Cerebellum Cerebral cortex Child Citric Acid Cycle Cognitive deficits Competence Complex Congenital Abnormality Consumption Cortical Malformation Cues Cytoplasmic Granules Data Defect Development Diabetes Mellitus Dimensions Dorsal Drosophila genus Drug Prescriptions Embryo Energy Metabolism Epilepsy Eukaryotic Cell Exhibits Fetus Forebrain Development Generations Genetic Genus Hippocampus Gestational Diabetes Glucose Glutamine Glutathione Disulfide Glycolysis Growth and Development function Guanosine Triphosphate Heterogeneity High Pressure Liquid Chromatography Homeostasis Immigration Immunohistochemistry In Vitro Intermediate Filaments Interneurons Knock-out Knockout Mice Label Lead Malnutrition Mammals Measurement Measures Mediating Mediator of activation protein Memory impairment Metabolic Metabolic Diseases Metabolism Metformin Methods Mitotic Molecular Mus Mutant Strains Mice NADH NMR Spectroscopy Neuraxis Neurodegenerative Disorders Neurons Nutrient Organism Oxidation-Reduction Pharmaceutical Preparations Phenotype Physiological Play Population Primates Process Prosencephalon Publishing Regulation Research Role Schizophrenia Stem cells Technology Telencephalon Testing Tissues Transcriptional Regulation Transgenic Mice Ventricular Work adenylate kinase base energy balance extracellular fetal hindbrain in vivo interest lissencephaly metabolomics migration mutant nerve stem cell nervous system disorder nestin protein neuroblast neurogenesis neuron apoptosis neuron loss novel novel therapeutics nutrient metabolism postnatal precursor cell prenatal progenitor progressive neurodegeneration protein kinase modulator sensor small molecule tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mammalian cortical development is a complex and tightly regulated process. While it is known that humoral and transcriptional regulation generates the cellular diversity in the mammalian telencephalon, a relatively unexplored area is whether the progenitor populations are also metabolically distinct and the extent to which metabolic regulation of precursor cells contribute to neurogenesis in the telencephalon. AMP- activated protein kinase (AMPK) is an energy sensor and plays a central role in energy and redox homeostasis in all eukaryotic cells. Recent studies show, that AMPK controls many fundamental processes including regulation of cell structures, polarity, cell division, migration and normal growth and development of organisms. In this application we will test our hypothesis that AMPK regulates neurogenesis in the telencephalon though its energy sensing functions. AMPK exists as a heterotrimer of catalytic ¿ and regulatory ¿ and ? subunits. Mammals express 2¿, 2¿ and 3? subunits. Not much is known about AMPK function in neural cells. Studies in Drosophila demonstrate that AMPK is necessary for maintaining mitotic competence of neural precursors and loss of AMPK function also causes progressive neurodegeneration. Our published study (Dev. Cell, 2009) in the germline ¿1 mutant mice shows massive apoptosis, which was primarily restricted to the intermediate progenitors (IPCs and their progeny) of developing telencephalon in the prenatal embryo, while in the postnatal brain apoptosis was restricted to the external granule layer of the developing cerebellum. In vitro analysis showed cell-intrinsic G2M-specific defects and apoptosis of ¿1 mutant neural precursors. In this application, we will focus on the telencephalon. With the help of our recently generated ¿1 conditional knockout mouse and other transgenic mice, we will conduct bioenergetics studies to examine whether metabolic uniqueness of dorsal and ventral telencephalon IPCs render them more sensitive to loss of AMPK function during their proliferation, survival, migration and differentiation (Aim1). We will examine regional control of neurogenesis by ¿1 in the dorsal and ventral telencephalon in vivo, by using region-specific Cre lines to reduce ¿1 function (Aim2). In Aim3, we will use three cutting edge technologies to investigate region-specific tissue bioenergetics and metabolomics in the intact brain in vivo. We expect that our studies will provide new dimensions to our understanding of cortical development in the light of cellular metabolism. Identification of novel AMPK effectors and AMPK subunit-specific small molecule modulators could one day potentially lead to novel therapeutics for neurodegenerative and metabolic diseases.

描述（由申请人提供）：哺乳动物皮质发育是一个复杂且严格调控的过程，虽然已知体液和转录调节产生哺乳动物端脑的细胞多样性，但相对未探索的领域是祖细胞群体是否在代谢上也具有独特性和多样性。前体细胞的代谢调节对端脑神经发生的贡献程度 AMP 激活蛋白激酶 (AMPK) 是一种能量传感器，在能量和氧化还原中发挥着核心作用。最近的研究表明，AMPK 控制着许多基本过程，包括细胞结构、极性、细胞分裂、迁移以及生物体正常生长和发育的调节。端脑虽然其能量传感功能作为催化的异三聚体存在。和监管和 ? 亚基表达 2¿ , 2¿关于神经细胞中的 AMPK 功能知之甚少。果蝇研究表明，AMPK 对于维持神经前体细胞的有丝分裂能力是必需的，而 AMPK 功能的丧失也会导致进行性神经变性（Dev. Cell，2009）。）在种系 ¿ 1突变小鼠表现出大量细胞凋亡，主要局限于产前胚胎发育中的端脑的中间祖细胞（IPC及其后代），而在出生后的脑细胞凋亡则局限于发育中小脑的外部颗粒层。显示细胞固有的 G2M 特异性缺陷和 ¿ 1 突变神经前体在这个应用程序中，我们将在我们最近生成的帮助下关注端脑。 1 条件敲除小鼠和其他转基因小鼠，我们将进行生物能学研究，以检查背侧和腹侧端脑 IPC 的代谢独特性是否使它们在增殖、存活、迁移和分化过程中对 AMPK 功能的丧失更加敏感（我们将检查）。神经发生的区域控制1 在体内的背侧和腹侧端脑中，通过使用区域特异性 Cre 系来减少 ¿在 Aim3 中，我们将使用三种尖端技术来研究体内完整大脑中的区域特异性组织生物能学和代谢组学，我们希望我们的研究将为我们理解皮质发育提供新的维度。新型 AMPK 效应子和 AMPK 亚基特异性小分子调节剂的鉴定有一天可能会带来神经退行性和代谢疾病的新疗法。