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：
9130292
负责人：
Biplab Dasgupta
金额：
$ 33.47万
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/9130292
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 α and regulatory ß and γ subunits. Mammals express 2α, 2ß and 3γ 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 ß1 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 ß1 mutant neural precursors. In this application, we will focus on the telencephalon. With the help of our recently generated ß1 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 ß1 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（由适用提供）：哺乳动物皮质发育是一个复杂且严格调节的过程。尽管众所周知，体液和转录调控会在哺乳动物端脑中产生细胞多样性，但相对出乎意料的区域是祖细胞种群是否也是代谢性的，以及前体细胞的代谢调节的程度有助于端脑中神经发生。 AMP激活的蛋白激酶（AMPK）是一种能量传感器，在所有真核细胞中都起着核心作用，在能量和氧化还原稳态中起着核心作用。最近的研究表明，AMPK控制着许多基本过程，包括调节细胞结构，极性，细胞分裂，迁移以及生物的正常生长以及生物的发育。在此应用中，我们将测试我们的假设，即AMPK通过其能量敏感性功能来调节尾脑中神经发生。 AMPK作为催化α和调节β和γ亚基的异三聚体存在。哺乳动物表达2α，2ß和3γ亚基。关于神经元细胞中AMPK功能的知之甚少。果蝇的研究表明，AMPK对于维持神经元前体的有丝分裂能力和AMPK功能的丧失是必要的，还会导致渐进性神经变性。我们在生殖线ß1突变小鼠中发表的研究（Dev。Cell，2009）显示了大量的凋亡，体外分析显示了细胞内部G2M特异性缺陷和ß1突变神经元前体的细胞凋亡。在此应用程序中，我们将重点关注端脑。借助我们最近产生的ß1条件敲除小鼠和其他转基因小鼠，我们将进行生物能力研究，以检查背侧和腹侧端脑的代谢唯一性是否使它们在其增殖，生存，迁移和差异化过程中对AMPK功能的丧失更为敏感（AIM1）。我们将通过使用区域特异性的CRE系来降低ß1功能（AIM2），在体内对1中对1个神经发生的区域控制。尖端技术研究了体内完整大脑中特定区域的组织生物能学和代谢组学。我们预计，根据细胞代谢，我们的研究将为我们对皮质发育的理解提供新的方面。新型AMPK效应和AMPK亚基特异性小分子调节剂的鉴定可能有一天可能导致神经退行性和代谢疾病的新型治疗。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism.

DOI：
10.1038/ncomms5993
发表时间：
2014-09-26
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Pooya, Shabnam;Liu, Xiaona;Kumar, V. B. Sameer;Anderson, Jane;Imai, Fumiyasu;Zhang, Wujuan;Ciraolo, Georgianne;Ratner, Nancy;Setchell, Kenneth D. R.;Yutaka, Yoshida;Jankowski, Michael P.;Dasgupta, Biplab
通讯作者：
Dasgupta, Biplab

The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent.