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（由适用提供）：我们的总体目标是了解妊娠最后三个月早期出生的发育性脑疾病，尤其是少突牙术祖细胞对损伤的适应性反应，这些细胞在这段时间内丰富的细胞，并分化为形成白质细胞的细胞。当婴儿是早产且出生体重低的时候，发育中的大脑中白质损伤的临床后果是大脑麻痹。该疾病的特征是运动控制的终生异常，导致痉挛，使日常生活或行走的活动变得困难。虽然白质损伤与缺氧 - 缺血性的关联有充分的证明，但对白质降低的机制却鲜为人知。我们和其他人表明，缺氧 - 异常会影响少突胶质祖细胞的增加，但缺乏白质。反映我们对疾病的不良理解的是缺乏针对有风险的婴儿的特定疗法。识别microRNA作为基因表达的重要调节剂，使其成为开发新治疗干预措施的主要目标。目前，我们对少突胶质细胞命运承诺和分化的microRNA调节的理解是基本的。我们的初步数据支持了一个假设，即microRNA调节我们将基于初步数据，以机械地破译microRNAS如何调节寡头胶质发育以响应损伤。通过我们的研究，我们试图探索以前未知的途径对围产期低氧 - 缺血性缺血的寡头反应。 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功能实验，这种模态可以转化为临床用途。我们的数据不仅会阐明对损伤的寡胶质体适应的分子基础，而且还可能为早产婴儿的新疗法奠定了面临脑瘫风险的新疗法，即microRNA Mimetics和“ Antagomirs”。