Erythropoietin and Neurogenesis after Neonatal Stroke

描述(由申请人提供)：这是对费尔南多·冈萨雷斯博士的K08奖项的申请，费尔南多·冈萨雷斯博士是加州大学旧金山分校(UCSF)新生儿科的儿科学助理教授，他正在确立自己作为新生儿大脑开发和修复方面的初级研究员的地位。这个K08奖项将为Gonzalez博士提供完成下列目标所需的支持：(1)确定在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、细胞命运和功能结局的影响；(3)获得基础神经生物学和干细胞生物学方面的专业知识，使他能够研究神经干细胞在未成熟大脑中的调节、分化和功能；以及(4)获得规划和实施基础科学翻译研究方面的专业知识，从而发展作为翻译研究员的独立研究生涯。为了实现这些目标，冈萨雷斯博士组建了一个指导团队，成员包括主要赞助人和导师、加州大学旧金山分校神经学和儿科教授唐娜·费里罗博士(Donna Ferriero)，他是新生儿脑损伤基础科学和临床研究的领先专家，以及两名科学顾问：加州大学旧金山分校儿科副教授帕特里克·麦克奎伦(Patrick McQuillen)博士，他在表征缺氧缺血性脑损伤后皮质发育和选择性易损性机制方面拥有丰富经验，是脑损伤立体技术和纵向研究方面的专家；和Zinaida Vexler博士，他是加州大学旧金山分校神经病学教授兼新生儿脑疾病中心研究主任，研究中风对细胞因子信号和炎症的影响，在荧光成像和标记技术方面经验丰富。冈萨雷斯博士还将听取一个小组的建议，小组成员包括新生儿科主任、霍华德·休斯医学研究所研究员大卫·罗维奇博士，以及加州大学旧金山分校再生医学和干细胞研究广泛中心主任阿诺德·克里格斯坦博士，他将负责跟踪冈萨雷斯的进展，并提供与干细胞生物学相关的研究设计和执行方面的意见。卒中引起的脑缺血再灌注损伤是新生儿疾病的重要原因，目前对此知之甚少。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的正常过程，对损伤的反应，以及外源性治疗如何增强修复。这里提出的研究旨在回答这样一个问题：NSC的命运能否被改变以改善新生儿中风后的长期结果？Gonzalez博士将利用他在加州大学旧金山分校的现有资源：确定NSC的发展以及对新生儿中风和EPO治疗的反应(目标1)，阐明对可进一步增强功能的替代的、更临床相关的外源性EPO剂量方案的长期反应(目标2)，并确定促进EPO修复的重要信号通路、机制和时机(目标3)。这将为冈萨雷斯博士提供必要的技能和初步数据，以准备R01拨款申请，他将最终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和命运的操纵转化为临床治疗。

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.