HIF Mediated Oxygen Sensing in Oligodendrocyte Development and Brain Injury

HIF 介导的少突胶质细胞发育和脑损伤中的氧感应

基本信息

批准号：
8203289
负责人：
John C Silbereis
金额：
$ 2.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8203289
关键词：
Acute Alleles Animal Model Animals Apnea Axon Biological Assay Biology Brain Brain Diseases Brain Injuries Bronchopulmonary Dysplasia Cardiovascular Diseases Cause of Death Cell Culture Techniques Cell Death Cell Hypoxia Cells Cerebral Palsy Chronic Coculture Techniques Coupled Development Differentiation and Growth Ensure Fibroblast Growth Factor Gene Expression Genetic Genetic Recombination Gestational Age Goals Growth Factor Histology Homeostasis Human Hydroxyl Radical Hyperoxia Hypotension Hypoxia Hypoxia Inducible Factor Hypoxic Brain Damage Impairment In Vitro Incidence Infant Injection of therapeutic agent Injury Learning Light Maintenance Malignant Neoplasms Mediating Mediator of activation protein Mentorship Mus Mutant Strains Mice Myelin Neonatal Neonatal Brain Injury Neonatology Neurons Nuclear Oligodendroglia Oxygen Oxygen measurement, partial pressure, arterial Pathogenesis Pathology Perinatal Hypoxia Platelet-Derived Growth Factor Play Pregnancy Premature Birth Procollagen-Proline Dioxygenase Prosencephalon Proteins Psyche structure Recovery Regulation Relative (related person)Research Respiratory distress Role Schedule Signal Transduction Site Stroke Tamoxifen Testing Third Pregnancy Trimester Training Transgenic Mice Transgenic Organisms United States Work brain cell career glial cell development hypoxia inducible factor 1 hypoxia neonatorum in utero in vivo mouse model multicatalytic endopeptidase complex myelination neonate oligodendrocyte lineage oligodendrocyte precursor postnatal premature pup research study response translational neuroscience white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): White matter injury associated with prematurity is currently the leading cause of cerebral palsy. Oligodendrocytes, the myelinating cells of the brain, are thought to be vulnerable to hypoxic damage in very preterm human neonates (24-32 weeks gestational age). Oxygenation in such infants may be severely disrupted due to either hypoxia (e.g., from respiratory distress, hypotension) or relative hyperoxia (e.g., PaO2 ~60-80 in NICU versus PaO2 ~30-40 in utero.) Elucidating the mechanisms that underlie the response of mature and immature oligodendrocytes to hypoxia will thus greatly advance our understanding of developmental white matter injury. This proposal details a 3 year plan for doctoral dissertation research under the mentorship of Dr. David Rowitch. The fellow will investigate the role of hypoxia and Hypoxia Inducible Factors, the principle transcriptional mediators of the cellular hypoxia response, in normal oligodendrocyte development and a mouse model of chronic neonatal hypoxic brain injury. The fellow will utilize and further develop his expertise in histology, oligodendrocyte cell culture techniques, mouse genetics, and neurostereology to accomplish these goals through the following specific aims: 1.) To determine the regulation of wild type oligodendrocyte lineage proliferation and differentiation by hypoxia in vitro and in vivo; 2.) To determine whether Hypoxia Inducible Factor (HIF) signaling is critical for oligodendrocyte development; 3.) To determine the contribution of Hypoxia Inducible Factor signaling to chronic neonatal hypoxic brain injury. The expertise of Dr. Rowitch in white matter injury, glial development, and neonatology, coupled with the advice of our collaborator Dr. Emin Maltepe an expert on HIF biology, will provide the intellectual and technical guidance necessary to ensure successful completion of these aims. The research plan proposed here along with the fellow's choice of mentorship will provide excellent training towards the fellow's goal of an academic career in developmental neuroscience and translational brain injury research.

描述（由申请人提供）：与早产相关的白质伤害目前是脑瘫的主要原因。少突胶质细胞是大脑的髓细胞，被认为在人类新生儿（24-32周胎龄）中容易受到低氧损害的影响。由于缺氧（例如，呼吸窘迫，低血压）或相对高氧（例如，NICU中的PAO2〜60-80）在NICU中与PAO2〜30-40相对于子宫内的PAO2〜60-80，可能会严重破坏此类婴儿的氧合作用。受伤。该提案详细介绍了大卫·罗奇（David Rowitch）博士的指导下的3年博士学位论文研究计划。该研究员将研究缺氧和缺氧诱导因素的作用，细胞缺氧反应的主要转录介质，在正常的寡胶质细胞发育中以及慢性新生儿缺氧性脑损伤的小鼠模型中的作用。该研究员将利用并进一步发展他在组织学，少突胶质细胞培养技术，小鼠遗传学和神经学的专业知识中，通过以下特定目的来实现这些目标：1。）确定野生型少突胶质细胞素质扩散和对野生型的野生型少突胶质素质扩散以及在体内较低的远低氧; 2.）确定缺氧诱导因子（HIF）信号是否对于少突胶质细胞的发育至关重要； 3.）确定缺氧诱导因子信号传导对慢性新生儿缺氧脑损伤的贡献。 Rowitch博士在白质损伤，神经胶质开发和新生儿学方面的专业知识，再加上我们合作者Emin Maltepe博士的HIF生物学专家Emin Maltepe博士的建议，将提供确保成功完成这些目标所必需的知识和技术指导。在这里提出的研究计划以及同伴的指导选择将为同胞在发育神经科学和转化脑损伤研究方面的学术生涯的目标提供出色的培训。