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）：与早产相关的白质损伤目前是脑瘫的主要原因。少突胶质细胞（大脑的髓鞘形成细胞）被认为在极早产人类新生儿（胎龄 24-32 周）中很容易受到缺氧损伤。此类婴儿的氧合可能因缺氧（例如，呼吸窘迫、低血压）或相对高氧（例如，NICU 中的 PaO2 ~60-80 与子宫内的 PaO2 ~30-40）而受到严重干扰。因此，成熟和未成熟少突胶质细胞对缺氧的反应将极大地促进我们对发育性白质损伤的理解。该提案详细介绍了在 David Rowitch 博士的指导下进行博士论文研究的 3 年计划。该研究员将研究缺氧和缺氧诱导因子（细胞缺氧反应的主要转录介质）在正常少突胶质细胞发育和慢性新生儿缺氧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、小鼠遗传学和神经体视学方面的专业知识，通过以下具体目标来实现这些目标：1.) 确定缺氧对野生型少突胶质细胞谱系增殖和分化的调节体外和体内； 2.) 确定缺氧诱导因子 (HIF) 信号传导是否对少突胶质细胞发育至关重要； 3.) 确定缺氧诱导因子信号传导对慢性新生儿缺氧性脑损伤的影响。 Rowitch 博士在白质损伤、神经胶质发育和新生儿学方面的专业知识，加上我们的合作者、HIF 生物学专家 Emin Maltepe 博士的建议，将为确保成功完成这些目标提供必要的知识和技术指导。这里提出的研究计划以及该研究员选择的导师将为该研究员在发展神经科学和转化性脑损伤研究方面的学术生涯目标提供良好的培训。