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Cerebrospinal fluid proteome mediated signaling in the developing CNS

发育中的中枢神经系统中脑脊液蛋白质组介导的信号传导

基本信息

批准号：
8599494
负责人：
MARIA LEHTINEN
金额：
$ 24.06万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599494
关键词：
Adult Affect Age Aging Area Arts Award Bathing Biochemical Genetics Brain Brain region Breathing Caenorhabditis elegans Cell Proliferation Cell Survival Cells Cerebrospinal Fluid Cerebrum Cessation of life Cilia Commit Complement Cues Cyclic AMP Data Development Developmental Biology Diagnostic Disease Doctor of Philosophy Electroporation Embryo Environment Erinaceidae Experimental Models Feedback Finland Foundations Future Genes Genetic Glial Fibrillary Acidic Protein Goals Growth Growth Factor Health Homeostasis Human Hypothyroidism Immune Sera In Vitro Institutes Insulin-Like Growth Factor II Joints Journals Laboratories Laboratory Research Learning Life Location Mass Spectrum Analysis Mediating Mentors Molecular Mus Myoclonic Epilepsies Nerve Degeneration Neuroepithelial Neuroglia Neurologic Neurons Neurosciences Oxidation-Reduction Pattern Pennsylvania Phase Play Positioning Attribute Postdoctoral Fellow Process Proliferating Proteins Proteome Regulation Research Role Schools Scientist Signal Pathway Signal Transduction Signaling Molecule Solid Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stem cells Structure of choroid plexus Supplementation Surface System Techniques Testing Therapeutic Time Training Transgenic Mice Tretinoin Universities Validation Ventricular abstracting career cell behavior developmental neurobiology experience improved in utero in vivo interest meetings mouse model nerve stem cell nervous system disorder neuroepithelium neurogenesis neuroregulation novel diagnostics novel therapeutic intervention progenitor programs receptor research and development research study skills stem stem cell niche undergraduate education undergraduate research

项目摘要

Project Summary/Abstract My interest in diseases of the nervous system stems from my undergraduate education at the University of Pennsylvania, where as a Wistar Institute undergraduate fellow with Dr. Art McMorris, I investigated extrinsic cues triggering cAMP signaling in glia. As an undergraduate research fellow at Rockefeller University in Dr. Bruce McEwen's laboratory, I investigated how hypothyroidism altered signaling molecules in the brain. These experiences led me to graduate school at Harvard University, where I trained with Dr. Azad Bonni in molecular neuroscience and elucidated signaling pathways that mediate survival and death signaling in mammalian neurons and in vivo in C. elegans. Upon completion of my PhD, I carried out my early postdoctocal training with Dr. Anna-Elina Lehesjoki at the Folkh¿lsan Institute of Genetics in Helsinki, Finland, where I discovered that impaired redox homeostasis is a key mechanism triggering neurodegeneration in the progresive myoclonus epilepsy, Unverricht-Lundborg disease (EPM1). From these research experiences, I have gained experience in molecular neuroscience and its applications to neurologic disease. I joined Dr. Chris Walsh's lab for my second postdoc, in hopes that comprehensive training in developmental neurobiology during the mentored phase of this award would complement my training in molecular neuroscience, and provide unique perspective on the mechanisms underlying neurologic disease throughout life. Dr. Walsh's is a leader in the field of cerebral cortical development research. I will learn fundamental techniques in the lab, ranging from quantitative histological analyses to in utero electroporations. Dr. Walsh has assembled a highly talented group of scientists, which will continue to provide a unique source of support and inspiration in informal conversations and weekly lab meetings and journal clubs. The Walsh lab is located in the Division of Genetics, which also hosts joint weekly data talks with the Division of Neuroscience, to promote collaborative exchanges and assistance with technical and theoretical isues. This intellectually engaging environment will provide an excellent source of discussion and feedback during the mentored phase of the award. Importantly, the Division of Genetics is committed to supporting the transition of postdocs to independent research positions. To this end, I will attend a number of career training seminars and meetings geared at preparing me for launching my independent research career. The long-term goal of my research is to elucidate how the cerebrospinal fluid (CSF) functions as a signaling niche that coordinates a rich interaction of signaling factors, acting at long distances to regulate target cell behavior during health and disease. During cerebral cortical development, rapid changes in proliferating progenitor cells occur almost synchronously across vast areas of the neuroepithelium. The protracted location of neuroepithelial cilia in the CSF suggests a potential role for the CSF as a source of extrinsic signals guiding progenitor proliferation. Since the CSF turns over several times per day, the CSF-choroid-plexus system is ideally suited for triggering rapid and spatially synchronized changes in molecular signaling across large distances. My immediate research goal in this proposal is to investigate the role of embryonic CSF proteome in regulating cortical progenitor proliferation during development. The experiments in Aim1 will use heterochronic explants and cultured stem cells to test the ability of CSF to support the survival, growth, and proliferation of cortical progenitor cells. Since the CSF contains hundreds of proteins, I will then use biochemical and genetic approaches to examine how Igf2 (Insulin-like growth factor 2), a candidate factor identified in our preliminary mass spectrometry analyses, may be actively distributed by the CSF to influence progenitor proliferation (Aim 2). The mentored phase of the award (Aims 1&2) will help refine the experimental models, techniques, and professional skills needed to launch a successful, independent research program examining the mechanisms by which CSF-distributed factors influence target cells in health and disease. The fundamental techniques including neurosphere cultures, quantitative histological analyses, and in utero electroporations, all learned during Aims 1&2, wil prepare me for the experiments proposed in Aim 3, which will explore the roles and mechanisms by which other CSF-borne signaling factors, such as retinoic acid and Sonic hedgehog, are regulated by the CSF to act on target cells at the ventricular surface. By the end of this award period, my independent research laboratory wil have pioneered a new concept in developmental biology in which the CSF plays an active role in cerebral cortical development. The proposed experiments represent a solid foundation for future studies investigating changes in the CSF stem cell niche in aging and age-associated neurologic disease. Since the CSF is a surgically accessible medium in humans and mouse models, the proposed experiments will pave the way towards development of powerful diagnostic and therapeutic approaches.

项目摘要/摘要我对神经系统疾病的兴趣源于我在加州大学的本科教育在宾夕法尼亚州，作为阿特·麦克莫里斯博士的维斯塔尔研究所本科生，我研究了外在的触发神经胶质细胞内cAMP信号的信号。作为洛克菲勒大学的本科生研究员，布鲁斯·麦克尤恩的实验室，我研究了甲状腺功能减退症是如何改变大脑中的信号分子的。这些这些经历让我去了哈佛大学研究生院，在那里我和阿扎德·邦尼博士一起接受了分子方面的培训神经科学和阐明哺乳动物中介导生存和死亡信号的信号通路线虫的神经元和活体。博士毕业后，我开始了早期的博士后培训与芬兰赫尔辛基Folkhülsan遗传学研究所的Anna-Elina Lehejoki博士一起，我在那里发现了氧化还原动态平衡受损是引发进展性神经退行性变的关键机制肌阵挛癫痫，Unverricht-Lundborg病(EPM1)。从这些研究经验中，我学到了一些东西分子神经科学及其在神经系统疾病中的应用经验。我加入了克里斯·沃尔什博士的实验室对于我的第二个博士后，我希望在这个奖项的指导阶段将补充我在分子神经科学方面的培训，并提供独特的透视终生神经疾病的潜在机制。沃尔什博士的研究在大脑皮层发育研究领域处于领先地位。我要学习基础知识实验室中的技术，从定量组织分析到宫内电穿孔。沃尔什博士已经聚集了一群才华横溢的科学家，他们将继续提供独特的支持和在非正式对话、每周实验室会议和杂志俱乐部中获得灵感。沃尔什实验室位于遗传学部也与神经科学部每周举办一次数据会谈，以促进与技术和理论机构进行协作交流和协助。这在智力上很吸引人环境将在指导阶段提供极好的讨论和反馈来源获奖。重要的是，遗传学分部致力于支持博士后向独立研究职位。为此，我将参加一些职业培训研讨会和会议为开启我的独立研究事业做好准备。我研究的长期目标是阐明脑脊液(CSF)是如何发挥作用的信号利基，协调信号因子的丰富相互作用，远距离作用于调节靶点健康和疾病期间的细胞行为。在大脑皮层发育过程中，细胞增殖的快速变化祖细胞几乎同步地出现在神经上皮的大片区域。延长的地点脑脊液中神经上皮纤毛的发现提示脑脊液作为外部信号引导来源的潜在作用祖细胞增殖。由于脑脊液每天翻转几次，脑脊液-脉络丛系统非常适合于触发分子信号的快速和空间同步变化距离。我在这项提议中的直接研究目标是研究胚胎脑脊液蛋白质组在在发育过程中调节皮质前体细胞的增殖。 Aim1的实验将使用异种外植体和培养的干细胞来测试脑脊液的能力以支持皮质祖细胞的存活、生长和增殖。因为脑脊液中含有数百个然后，我将使用生化和遗传方法来研究Igf2(胰岛素样生长因子)是如何 2)，在我们的初步质谱分析中确定的候选因子可能通过以下方式活跃地分布脑脊液影响祖细胞增殖(目标2)。该奖项的指导阶段(目标1和2)将有所帮助完善实验模型、技术和专业技能，以启动成功的、研究脑脊液分布因素影响靶点的机制的独立研究项目健康和疾病中的细胞。基本技术包括神经球培养，定量组织学分析和宫内电穿孔，都是在目标1和2中学到的，这将使我为目标3中提出的实验，将探索其他脑脊液携带的作用和机制信号因子，如维甲酸和Sonic Hedgehog，由CSF调节作用于靶细胞脑室表面。到这个获奖期结束时，我的独立研究实验室将有开创了发育生物学的新概念，即脑脊液在大脑皮层中发挥积极作用发展。拟议的实验为未来研究变化奠定了坚实的基础在衰老和老年相关神经疾病中的脑脊液干细胞利基。因为脑脊液是一种外科手术在人类和小鼠模型中，拟议的实验将为开发强大的诊断和治疗方法。