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: 8424312
• 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/8424312
• 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.

描述（由申请人提供）：这是一份申请K08奖的Fernando Gonzalez博士的申请，他是加州大学旧金山分校（UCSF）新生儿科儿科助理教授，他是一名研究新生儿大脑发育和修复的初级研究员。这项K08奖将为Gonzalez博士提供必要的支持，以实现以下目标：(1)识别在大脑发育中起主要作用的神经干细胞（NSC）；(2)确定新生儿卒中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，为研究未成熟大脑中NSCs的调控、分化和功能做准备；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事业。为了实现这些目标，冈萨雷斯博士组建了一个指导团队，其中包括一名主要发起人和导师，唐娜·费里耶罗博士，加州大学旧金山分校神经病学和儿科教授，他是新生儿脑损伤基础科学和临床研究方面的权威专家，以及两名科学顾问：Patrick McQuillen博士，加州大学旧金山分校儿科学副教授，在描述缺氧缺血性脑损伤后的皮质发育和选择性易感机制方面有着丰富的经验，是体视学技术和脑损伤纵向研究方面的专家；Zinaida Vexler博士，UCSF新生儿脑部疾病中心神经学教授和研究主任，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。冈萨雷斯博士还将接受一个专家组的建议，该专家组包括新生儿科主任、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Broad中心主任阿诺德·克里格斯坦博士，后者将负责跟踪冈萨雷斯博士的进展，并为与干细胞生物学相关的研究设计和执行提供意见。脑卒中引起的缺血性再灌注损伤是新生儿疾病的重要原因，目前对其了解甚少。为了最终解决新生儿早期中风后的特殊问题，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个问题：是否可以改变NSC的命运来改善新生儿中风后的长期预后？Gonzalez博士将利用UCSF提供给他的资源：表征NSC的发展和对新生儿中风和EPO治疗的反应（目标1），阐明对可能进一步增强功能的外源性EPO的替代的长期反应，更临床相关的给药方案（目标2），并确定EPO增强修复的重要信号通路，机制和时间（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传导和命运的操纵转化为临床治疗。