Metabolic Control of Proliferation and Differentiation in Oligodendrocytes

少突胶质细胞增殖和分化的代谢控制

基本信息

批准号：
10315354
负责人：
Sami Sauma
金额：
$ 3.17万
依托单位：
ADVANCED SCIENCE RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10315354
关键词：
ATP Citrate (pro-S)-Lyase Ablation Acetyl Coenzyme A Address Appointment Area Bioinformatics Biology Brain Cell Cycle Cell Differentiation process Cell Nucleus ChIP-seq Cholesterol Communication Cytosol Data Data Analyses Detection Development Diet Differentiated Gene Diffuse Disease Electron Microscopy Elements Endoplasmic Reticulum Epigenetic Process Experimental Designs Fatty Acids Fellowship Fostering Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Glucose Goals Grant Histone Acetylation Histone Deacetylation Histones Image Imaging technology Impairment In Vitro Institution International Lead Learning Light Lipids Maintenance Manuscripts Mass Spectrum Analysis Membrane Mental disorders Mentors Metabolic Metabolic Control Metabolism Methodology Mission Molecular Mus Myelin Myelin Sheath National Institute of Neurological Disorders and Stroke Nuclear Oligodendroglia Oral Outcome Pharmacology Phenotype Postdoctoral Fellow Process Proliferating Public Health Publications Publishing Regulation Reporting Research Rest Role Science Scientist Solid Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Students System Testing Training Transcript Transgenes Transgenic Organisms Undifferentiated United States National Institutes of Health Work base brain cell career cdc Genes chromatin immunoprecipitation epigenetic regulation gain of function genome-wide in vivo inhibitor/antagonist insight loss of function metabolic abnormality assessment myelination nervous system disorder novel therapeutics oligodendrocyte progenitor optogenetics overexpression postnatal progenitor repaired skills stem cells symposium synthetic enzyme transcriptome sequencing undergraduate student white matter

ATP Citrate (pro-S)-Lyase Ablation Acetyl Coenzyme A Address Appointment Area Bioinformatics Biology Brain Cell Cycle Cell Differentiation process Cell Nucleus ChIP-seq Cholesterol Communication Cytosol Data Data Analyses Detection Development Diet Differentiated Gene Diffuse Disease Electron Microscopy Elements Endoplasmic Reticulum Epigenetic Process Experimental Designs Fatty Acids Fellowship Fostering Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Glucose Goals Grant Histone Acetylation Histone Deacetylation Histones Image Imaging technology Impairment In Vitro Institution International Lead Learning Light Lipids Maintenance Manuscripts Mass Spectrum Analysis Membrane Mental disorders Mentors Metabolic Metabolic Control Metabolism Methodology Mission Molecular Mus Myelin Myelin Sheath National Institute of Neurological Disorders and Stroke Nuclear Oligodendroglia Oral Outcome Pharmacology Phenotype Postdoctoral Fellow Process Proliferating Public Health Publications Publishing Regulation Reporting Research Rest Role Science Scientist Solid Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Students System Testing Training Transcript Transgenes Transgenic Organisms Undifferentiated United States National Institutes of Health Work base brain cell career cdc Genes chromatin immunoprecipitation epigenetic regulation gain of function genome-wide in vivo inhibitor/antagonist insight loss of function metabolic abnormality assessment myelination nervous system disorder novel therapeutics oligodendrocyte progenitor optogenetics overexpression postnatal progenitor repaired skills stem cells symposium synthetic enzyme transcriptome sequencing undergraduate student white matter

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项目摘要

Project Summary Myelin is critical for proper brain function and its dysfunction, damage or inappropriate formation has been reported in a wide range of neurological and psychiatric disorders, thereby urging the discovery of new potential treatments. This fellowship addresses the role of metabolism, and more specifically of glucose-derived acetyl- CoA (AcCoA), in regulating developmental myelination. The experimental aims rest on the solid premise that AcCoA is an unstable compound which cannot freely diffuse from one compartment to the next. The overarching hypothesis is that AcCoA function is dependent on the subcellular localization of its synthetic enzyme ATP citrate lyase (ACLY) and on the levels of the specific AcCoA transporter to the endoplasmic reticulum, SLC33A1. Aim 1 uses loss- and gain-of-function approaches to test the hypothesis that high glucose levels during the first postnatal week favor nuclear localization of ACLY and in turn promote synthesis of AcCoA and its incorporation into histones, thereby resulting in the expression of genes that favor proliferation and the maintenance of the progenitor state. It also posits that the transient decline of glucose during the second postnatal week is responsible for decreased nuclear ACLY, decreased nuclear AcCoA thereby favoring histone deacetylation and the transition of OPC from proliferating to differentiating cells. The hypothesis will be tested using Acly loss- and gain-of-function approaches in vitro in cultured OPC as well as lineage specific ablation in mice. The genome wide distribution of select histone acetylation marks will be tested using chromatin immunoprecipitation. Aim 2 uses loss- and gain-of-function approaches to test the hypothesis that increased cytosolic AcCoA synthesis in differentiating OL, followed by its transport to the endoplasmic reticulum (via SLC33A1) is crucial for the synthesis of cholesterol and myelin lipids. This hypothesis is supported by the detection of increased myelin in mice with systemic overexpression of the Slc33a1 transgene. The subaims will address OL differentiation and myelin development by matrix assisted laser desorption/ionization (MALDI) imaging, and electron microscopy. The training plan incorporates learning of new skills, such as advanced methodology in epigenetics, bioinformatics, lentiviral transduction, optogenetics and the latest in mass spectrometry imaging technologies. In addition, several opportunities will be offered to encourage training in experimental design, data analysis, as well as improvements in written and oral scientific communication and opportunities to mentor undergraduate students. Professional development opportunities will be available and participation in local, national, and international conferences will allow networking. As tangible milestones, the work is expected to result in two high quality, first author manuscripts as a doctoral trainee, and grant the opportunity to obtain a competitive post-doctoral appointment, leading to a career in academic science. This fellowship aligns the applicant’s long-term goal of studying metabolic regulation of brain cells, with the public health mission of NIH and NINDS to foster academic scientists and steward advances in our understanding of brain development and disease.

项目摘要髓鞘对于适当的大脑功能至关重要，其功能障碍，损害或不适当的形成一直报道了广泛的神经和精神疾病，从而敦促发现新的潜力治疗。该奖学金涉及代谢的作用，更具体地是葡萄糖衍生的乙酰基 - COA（ACCOA），在监管发育性髓鞘中。实验目标基于一个坚实的前提 ACCOA是一种不稳定的化合物，无法从一个隔间到另一个隔间自由扩散。总体假设是ACCOA功能取决于其合成酶ATP柠檬酸盐的亚细胞定位裂解酶（Acly）以及特异性ACCOA转运蛋白的水平，向内质网slc33a1。目的 1使用功能障碍和获得功能的方法来检验以下假设。产后周有利于Acly的核定位，进而促进Accoa及其就业的合成进入组蛋白，从而导致基因的表达，这些基因有利于增殖和维持祖细胞状态。它还认为，第二个星期后葡萄糖的短暂下降为负责改善核acly，改善核accoa，从而有利于组蛋白脱乙酰基化和 OPC从增殖到分化细胞的过渡。该假设将使用丙烯损失和在培养的OPC和小鼠中的谱系特异性消融中，功能收益在体外接近。基因组精选组蛋白乙酰化标记的广泛分布将使用染色质免疫沉淀进行测试。目标2 使用功能障碍和获取方法来检验以下假设，即增加胞质Accoa合成区分OL，然后将其转运到内质网（通过SLC33A1）对于合成至关重要胆固醇和髓脂脂质。通过检测到小鼠的髓磷脂的发现，该假设得到了支持 SLC33A1转换的全身过表达。 Subiaims将解决差异化和髓鞘基质辅助激光解吸/电离（MALDI）成像和电子显微镜的开发。这培训计划结合了新技能的学习，例如表观遗传学，生物信息学的高级方法论，慢病毒翻译，光遗传学和最新的质谱成像技术。此外，将提供一些机会，以鼓励实验设计，数据分析以及改善书面和口头科学沟通以及指导本科生的机会。专业开发机会将提供并参与本地，国家和国际会议将允许网络。作为切实的里程碑，预计这项工作将导致两种高质量，首先作者手稿是博士学位培训生，并授予获得竞争性博士后的机会任命，导致学术科学职业。该奖学金对齐申请人的长期目标通过NIH和NIND的公共卫生使命研究脑细胞的代谢调节，以促进学术科学家和管家进步我们对大脑发育和疾病的理解。