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: 8827425
• 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/8827425
• 关键词: Address; Adult; Aftercare; Animals; Applications Grants; Astrocytes; Astrocytosis; Award; Basic Science; 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; behavioral outcome; 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; 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）：这是申请K08奖，申请Fernando Gonzalez博士，他是加利福尼亚大学旧金山大学（UCSF）的新生儿学助理教授（UCSF），他正在确定自己是新生儿大脑开发和修复的初级研究员。该K08奖将为冈萨雷斯博士提供实现以下目标所需的支持：（1）确定在大脑发育中起着重要作用的神经干细胞（NSC）； （2）确定新生儿中风和外源红细胞生成素（EPO）治疗对细胞信号，细胞命运和功能结果的影响； （3）获得基本神经生物学和干细胞生物学方面的专业知识，这将使他准备研究NSC在未成熟大脑中的调节，分化和功能；最后，（4）为了获得计划和执行基础科学转化研究的专业知识，从而发展了独立的研究职业，作为转化研究者。 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缺氧 - 缺血性脑损伤后选择性脆弱性的机制，并且是立体技术和脑损伤纵向研究的专家；神经病学教授兼UCSF新生儿脑疾病中心研究主任Zinaida Vexler博士，他研究中风对细胞因子信号传导和炎症的影响，并且在荧光成像和标记技术中经验丰富。冈萨雷斯博士还将由一个小组建议，包括新生儿病学系主任戴维·罗奇（David Rowitch）博士，霍华德·休斯医学院（Howard Hughes Medical Institute）研究员，以及UCSF再生医学中心和干细胞研究中心主任阿诺德·克里格斯坦（Arnold Kriegstein）博士，他们将负责遵循他的进度和有关干细胞与干细胞生物学的投入的投入，并提供有关研究设计和执行型干细胞生物学的投入。中风造成的缺血性再灌注损伤是新生儿疾病的重要原因，知识渊博。为了最终解决早期中风后针对新生儿的特定问题，我们必须首先研究大脑发展，应对损伤以及如何通过外源治疗增强修复的正常过程。此处提出的研究旨在回答以下问题：NSC命运是否可以改变以改善新生儿中风后的长期结局？ Gonzalez博士将使用UCSF的他使用的资源来表征：NSC开发以及对新生儿中风和EPO治疗的反应（AIM 1），以阐明对替代性，更相关的外源EPO的替代性剂量方案的长期响应，这些方案可以进一步增强功能2），并确定重要的信号path和Timement and Epos，以增强了EPO，以实现EPO的良好机构和TIMENCENT（目标），以实现EPO，以实现epo and and intemans，以实现EPO的努力。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赠款应用，在该应用中，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环境的疗法。