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

• 批准号: 8481603
• 负责人: John C Silbereis
• 金额: $ 1.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481603
• 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

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是目前脑瘫的主要原因。少突胶质细胞，大脑的髓鞘细胞，被认为在非常早产的人类新生儿（24-32孕周）中容易受到缺氧损伤。这类婴儿的氧合可能因缺氧（如呼吸窘迫、低血压）或相对高氧（如新生儿重症监护病房PaO2 ~60-80，而子宫内PaO2 ~30-40）而严重中断。阐明成熟和未成熟少突胶质细胞对缺氧反应的机制将极大地促进我们对发育性白质损伤的理解。此提案详细说明了在David Rowitch博士指导下的3年博士论文研究计划。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、小鼠遗传学和神经立体学方面的专业知识，通过以下具体目标实现这些目标：探讨缺氧对野生型少突胶质细胞系增殖分化的调控作用；2.） 确定缺氧诱导因子（HIF）信号是否对少突胶质细胞发育至关重要；3.） 探讨缺氧诱导因子信号在新生儿慢性缺氧脑损伤中的作用。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Emin Maltepe博士（HIF生物学专家）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对导师的选择将为研究员在发育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。