Erythropoietin and Neurogenesis after Neonatal Stroke

新生儿中风后促红细胞生成素和神经发生

• 批准号: 8606661
• 负责人: Fernando Francisco Gonzalez
• 金额: $ 17.75万
• 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: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606661
• 关键词: Address; Adult; Aftercare; Animals; Applications Grants; Astrocytes; Astrocytosis; Award; Basic Science; Behavioral; Brain; Brain Diseases; Brain Injuries; California; Cell Count; Cell Death; Cells; Cellular biology; Clinical; Clinical Research; Cognition; Cytokine Signaling; Data; Development; Disease; Dose; Ensure; Environment; Erythropoiesis; Erythropoietin; Frequencies; Generations; Gliosis; Goals; Green Fluorescent Proteins; Hour; Image; Immunohistochemistry; Inflammation; Injury; Institutes; Ischemia; Ischemic-Hypoxic Encephalopathy; Knowledge; Label; Laboratories; Learning; Longitudinal Studies; MAPK3 gene; Measurement; Measures; Mediating; Medical; Medicine; Memory; Mentors; Mitogen-Activated Protein Kinases; Modeling; Monitor; Morbidity - disease rate; Natural regeneration; Nature; Neonatal; Neonatal Brain Injury; Neonatology; Neurobiology; Neurology; Neurons; Newborn Infant; Oligodendroglia; Outcome; Pediatric Neurology; Pediatrics; Perinatal; Phosphatidylinositols; Phosphotransferases; Play; Postnatal Care; Process; Proliferating; Protocols documentation; Public Health; Publishing; Rattus; Recruitment Activity; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Design; Research Personnel; Resources; Role; San Francisco; Sensorimotor functions; Severities; Signal Pathway; Signal Transduction; Stem Cell Development; Stem Cell Research; Stroke; System; Techniques; Testing; Therapeutic; Time; Training; Translating; Translational Research; Universities; Ventricular; angiogenesis; brain repair; brain volume; career; clinically relevant; cytokine; design; disability; experience; functional outcomes; improved; in vivo; injury and repair; intercellular communication; loss of function; migration; neonatal death; neonate; nerve stem cell; neurogenesis; perinatal stroke; precursor cell; prenatal; professor; public health relevance; repaired; research study; response; skills; stem cell biology; stem cell fate; treatment effect; treatment strategy

DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Fernando Gonzalez, an Assistant Professor of Pediatrics in the Division of Neonatology at the University of California, San Francisco (UCSF), who is establishing himself as a junior investigator in the development and repair of the newborn brain. This K08 award will provide Dr. Gonzalez with the support necessary to accomplish the following goals: (1) to identify neural stem cells (NSC) that play a major role in brain development; (2) to determine the effects of neonatal stroke and exogenous erythropoietin (EPO) treatment on cell signaling, cell fate, and functional outcome; (3) to gain expertise in basic neurobiology and stem cell biology that will prepare him to study the regulation, differentiation and function of NSCs in the immature brain; and finally, (4) to gain expertise in planning and executing basic science translational research, and thereby develop an independent research career as a translational investigator. To achieve these goals, Dr. Gonzalez has assembled a mentoring team comprised of a primary sponsor and mentor, Dr. Donna Ferriero, Professor of Neurology and Pediatrics at UCSF, who is a leading expert in basic science and clinical research of neonatal brain injury, and two scientific advisors: Dr. Patrick McQuillen, Associate Professor of Pediatrics at UCSF, who has extensive experience characterizing cortical development and mechanisms of selective vulnerability following hypoxic-ischemic brain injury and is an expert in stereological techniques and longitudinal studies of brain injury; and Dr. Zinaida Vexler, Professor of Neurology and Director of Research of the Neonatal Brain Disorders Center at UCSF, who studies effects of stroke on cytokine signaling and inflammation and is experienced in fluorescent imaging and labeling techniques. Dr. Gonzalez will also be advised by a panel that includes Dr. David Rowitch, Chief of the Division of Neonatology and a Howard Hughes Medical Institute Investigator, and Dr. Arnold Kriegstein, Director of the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, who will be responsible for following his progress and providing input regarding study design and execution related to stem cell biology. The ischemic- reperfusion injury caused by stroke is a significant cause of neonatal disease and is poorly understood. To ultimately address problems that are specific to newborns following early stroke, we must first study the normal process by which the brain develops, responds to injury, and how repair is enhanced by exogenous therapy. The studies proposed here are designed to answer the question: can NSC fate be altered to improve long-term outcomes after neonatal stroke? Dr. Gonzalez will use the resources available to him at UCSF to: characterize NSC development and the response to neonatal stroke and EPO treatment (Aim 1), to clarify the long-term response to alternative, more clinically relevant dosing protocols of exogenous EPO that may further enhance function (Aim 2), and to identify important signaling pathways, mechanisms and timing responsible for EPO enhancement of repair (Aim 3). This will provide Dr. Gonzalez the necessary skills and preliminary data to prepare an R01 grant application in which he will ultimately study the underlying mechanisms of neonatal brain injury and repair, and how manipulation of cell signaling and fate can be translated into therapies for the clinical setting. PUBLIC HEALTH RELEVANCE: Even in the era of improved prenatal monitoring and postnatal care, neonatal stroke remains a leading cause of neonatal death and disease, and represents a significant public health burden due to long-term disabilities that can result from it. The unique nature of the immature brain and neural stem cells in the newborn causes it to respond differently to early stroke and brain injury, a phenomenon that is poorly understood and greatly understudied. Defining the response of vital precursor cells in the brain to development and early stroke, and clarifying the mechanisms and timing of repair in response to exogenous therapy will help alleviate the burden of neonatal stroke by leading to the creation of better treatment strategies. These can then be tailored to the newborn brain, which will reduce the frequency and severity of poor outcomes in the newborn.

描述（由申请人提供）：这是 Fernando Gonzalez 博士的 K08 奖申请，Fernando Gonzalez 博士是加州大学旧金山分校 (UCSF) 新生儿科儿科助理教授，正在将自己定位为新生儿大脑发育和修复方面的初级研究员。该 K08 奖项将为 Gonzalez 博士提供实现以下目标所需的支持：（1）识别在大脑发育中发挥重要作用的神经干细胞（NSC）； (2) 确定新生儿中风和外源性促红细胞生成素 (EPO) 治疗对细胞信号传导、细胞命运和功能结果的影响； (3) 获得基础神经生物学和干细胞生物学方面的专业知识，为研究未成熟大脑中神经干细胞的调节、分化和功能做好准备；最后，（4）获得规划和执行基础科学转化研究的专业知识，从而发展作为转化研究者的独立研究生涯。为了实现这些目标，Gonzalez 博士组建了一个指导团队，由主要发起人和导师、加州大学旧金山分校神经病学和儿科教授 Donna Ferriero 博士（新生儿脑损伤基础科学和临床研究领域的领先专家）和两名科学顾问组成：加州大学旧金山分校儿科副教授 Patrick McQuillen 博士，在皮质发育特征方面拥有丰富的经验。 和缺氧缺血性脑损伤后选择性脆弱性的机制，是立体学技术和脑损伤纵向研究的专家； Zinaida Vexler 博士是加州大学旧金山分校神经病学教授兼新生儿脑部疾病中心研究主任，他研究中风对细胞因子信号传导和炎症的影响，在荧光成像和标记技术方面经验丰富。 Gonzalez 博士还将得到一个小组的建议，该小组成员包括新生儿科主任兼霍华德休斯医学研究所研究员 David Rowitch 博士，以及加州大学旧金山分校再生医学和干细胞研究中心主任 Arnold Kriegstein 博士，后者将负责跟踪 Gonzalez 博士的进展，并提供有关干细胞生物学相关研究设计和执行的意见。中风引起的缺血再灌注损伤是新生儿疾病的重要原因，但人们对此知之甚少。为了最终解决早期中风后新生儿特有的问题，我们必须首先研究大脑发育、对损伤做出反应的正常过程，以及如何通过外源性治疗增强修复。这里提出的研究旨在回答这个问题：能否改变 NSC 的命运以改善新生儿中风后的长期结局？ Gonzalez 博士将利用 UCSF 提供的资源来：描述 NSC 发育以及对新生儿中风和 EPO 治疗的反应（目标 1），阐明对可能进一步增强功能的替代性、临床更相关的外源 EPO 给药方案的长期反应（目标 2），并确定负责 EPO 增强修复的重要信号传导途径、机制和时机（目标 3）。这将为 Gonzalez 博士提供必要的技能和初步数据，以准备 R01 拨款申请，他最终将研究新生儿脑损伤和修复的潜在机制，以及如何将细胞信号传导和命运的操纵转化为临床治疗。 公共卫生相关性：即使在产前监测和产后护理得到改善的时代，新生儿中风仍然是新生儿死亡和疾病的主要原因，并且由于其可能导致的长期残疾而构成重大的公共卫生负担。新生儿未成熟的大脑和神经干细胞的独特性质导致其对早期中风和脑损伤的反应不同，人们对这种现象知之甚少，也没有充分研究。定义大脑中重要的前体细胞对发育和早期中风的反应，并阐明对外源性治疗的修复机制和时间安排，将有助于制定更好的治疗策略，从而减轻新生儿中风的负担。然后可以针对新生儿大脑进行定制，这将减少新生儿不良后果的频率和严重程度。