MicroRNAs and Perinatal Hypoxia-Ischemia

MicroRNA 与围产期缺氧缺血

基本信息

批准号：
9258512
负责人：
MARIA LUZ VALDECANAS DIZON
金额：
$ 33.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258512
关键词：
Anisotropy Astrocytes BMPR2 gene Birth Bone Morphogenetic Proteins Brain Brain Diseases Brain Hypoxia-Ischemia CSPG4 gene Cell Lineage Cells Cerebral Palsy Clinical Data Development Disease Down-Regulation Family Foundations Gene Expression Gene Expression Regulation Glial Fibrillary Acidic Protein Goals Homeostasis Hypoxia Inducible Factor Individual Injection of therapeutic agent Injury Lead Low Birth Weight Infant LoxP-flanked allele Magnetic Resonance Imaging Mediating Messenger RNA MicroRNAs Modality Modeling Molecular Motor Mus Mutant Strains Mice Myelin Newborn Infant Oligodendroglia Pathogenesis Pathway interactions Perinatal Perinatal Hypoxia Positioning Attribute Pregnancy Trimesters Premature Infant Preventive therapy Proteins Publishing Quantitative Reverse Transcriptase PCR RNA Regulation Regulator Genes Research Risk Role Sampling Signaling Protein Societies Spastic Stem cells Tamoxifen Testing Third Pregnancy Trimester Time Translations Walking base bone morphogenetic protein receptors design experience experimental study feeding improved functioning innovation knock-down loss of function mimetics motor control myelination nerve stem cell novel novel therapeutic intervention novel therapeutics overexpression postnatal premature progenitor protein expression public health relevance regenerative therapy response response to injury spasticity technology diffusion vector white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): Our overarching goal is to understand developmental brain disorders that result from birth early in the last trimester of pregnancy, especially the adaptive response to injury by oligodendroglial progenitors cells, those cells that are abundant during this time period and differentiate into cells that form white matter. The clinical consequence of white matter injury within the developing brain, as often occurs when babies are born preterm and at low birth weight, is cerebral palsy. This disease is characterized by a lifelong abnormality of motor control that results in spasticity, making activities of daily livinglike feeding oneself or walking difficult. Whereas the association of white matter injury with hypoxia-ischemia is well documented, the mechanisms underlying decreased white matter are poorly understood. We and others have shown that hypoxia-ischemia induces an increase in oligodendroglial progenitors yet a paucity of white matter. Reflective of our poor understanding of the disease is the absence of specific therapies for babies at risk. Recognition of microRNAs as important regulators of gene expression makes them prime targets for the development of new therapeutic interventions. Presently, our understanding of microRNA regulation of oligodendrocyte fate commitment and differentiation is rudimentary. Our preliminary data supports a hypothesis that microRNAs regulate the response of oligodendroglial progenitors to hypoxia-ischemia. We will build upon our preliminary data to mechanistically decipher how microRNAs regulate oligodendroglial development in response to injury. Through our studies we seek to explore previously unknown pathways in the oligodendroglial response to perinatal hypoxia-ischemia. Our proposal is unique, because (a) we focus on novel pathways of gene regulation that have not been evaluated in oligodendroglial lineage cells within the context of perinatal hypoxiaischemia, (b) we utilize innovative mouse mutants to establish a "cause and effect" relationship, not just mere associations, and (c) we utilize cutting edge technology of diffusion tensor magnetic resonance imaging to evaluate our gain and loss of function experiments, a modality that is amenable to translation into clinical use. Our data will not only illuminate the molecular underpinnings of oligodendroglial adaptation to injury, but may also lay the foundation for novel therapies for preterm babies at risk for cerebral palsy, namely microRNA mimetics and "antagomiRs".

描述（由申请人提供）：我们的首要目标是了解妊娠最后三个月早期出生引起的发育性脑部疾病，特别是少突胶质祖细胞对损伤的适应性反应，这些细胞在这段时间内丰富并分化发育中的大脑中白质损伤的临床后果是脑瘫，这种疾病经常发生在早产儿和低出生体重的婴儿身上。导致痉挛，使日常生活活动（例如进食或行走困难）在白质损伤与缺氧缺血之间的关联中已得到充分证明，但我们和其他人已经表明缺氧缺血引起白质减少的机制知之甚少。少突胶质细胞祖细胞数量增加，但白质缺乏，这反映了我们对这种疾病的了解不足，因为我们缺乏针对高危婴儿的特定疗法。目前，我们对 microRNA 调节少突胶质细胞命运决定和分化的认识还很初级，我们将以此为基础支持 microRNA 调节少突胶质细胞祖细胞的反应的假设。我们的初步数据从机制上解释了 microRNA 如何调节少突胶质细胞对损伤的反应。通过我们的研究，我们试图探索少突胶质细胞对损伤的反应中以前未知的途径。我们的提议是独特的，因为（a）我们专注于尚未在围产期缺氧缺血背景下的少突胶质细胞系细胞中进行评估的新基因调控途径，（b）我们利用创新的小鼠突变体建立了“因果关系，而不仅仅是关联，并且（c）我们利用扩散张量磁共振成像的尖端技术来评估我们的功能实验的获得和丧失，这是一种可以转化为临床的模式我们的数据不仅将阐明少突胶质细胞适应损伤的分子基础，而且还可能为有脑瘫风险的早产儿的新疗法（即 microRNA 模拟物和“antagomirs”）奠定基础。