Region-restricted astrocytes in neural circuit formation and function

神经回路形成和功能中的区域限制性星形胶质细胞

• 批准号: 8896876
• 负责人: Anna V Molofsky
• 金额: $ 18.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896876
• 关键词: Address; Adult; Afferent Neurons; Amyotrophic Lateral Sclerosis; Antibodies; Astrocytes; Autistic Disorder; Axon; Binding; Biology; Boxing; Brain; California; Cells; Cessation of life; Clinical; Coculture Techniques; Communication; Cues; Data; Dendrites; Development; Development Plans; Disease; Dorsal; Ectopic Expression; Electrophysiology (science); Embryo; EphA5 Receptor; Fragile X Syndrome; Functional disorder; Genes; Goals; Health; Heterogeneity; Huntington Disease; Immunohistochemistry; In Vitro; K-Series Research Career Programs; Knowledge; Label; Laboratories; Lead; Light; Location; Maps; Measures; Membrane; Mentors; Mentorship; Molecular; Molecular Profiling; Motor; Motor Neurons; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Pathology; Population; Positioning Attribute; Postdoctoral Fellow; Process; Proteins; Psychiatrist; Psychiatry; Reporter; Reporting; Research; Research Personnel; Rett Syndrome; Role; Running; San Francisco; Schizophrenia; Scientist; Semaphorin-3A; Sensory; Signal Transduction; Slice; Spinal Cord; Supporting Cell; Synapses; Testing; Time; Training; Universities; Ventral Roots; axon guidance; base; career; career development; in vivo; instructor; motor neuron function; neural circuit; neuropsychiatry; postnatal; postsynaptic; presynaptic; programs; promoter; research and development; synaptogenesis

DESCRIPTION (provided by applicant): Astrocytes (AS) are the most numerous cells in the central nervous system and are increasingly recognized as key players in the pathology of neurodevelopmental and neurodegenerative diseases including the autism- associated disorders Rett Syndrome and Fragile X syndrome, Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease. The goal of this research program is to define the role of AS in guiding the formation of functional neural circuits. The applicant for this K08 Mentored Clinical Scientist Research Career Development Award is a Psychiatrist and Clinical Instructor in the Department of Psychiatry, and a postdoctoral fellow with Dr. David Rowitch at the University of California San Francisco. This proposal outlines a 4-year career development plan and research strategy that includes mentorship by Dr. Rowitch, Dr. John Rubenstein and Dr. Erik Ullian to accomplish the research aims described below. Together, these will enable the applicant to fulfill a career goal of running an independent laboratory spanning the interface of glial biology and neuropsychiatric disease. Preliminary data that forms the basis for this proposal demonstrates that the guidance molecules Sema3a and EphA5 are uniquely expressed by ventral, but not dorsal spinal cord AS. AS-encoded Sema3a secreted from ventral AS has local effects on motor neuron position, postnatal survival, and synaptogenesis, demonstrating molecularly defined AS heterogeneity for the first time. The research strategy expands these findings in mechanistic and functional directions to determine how these heterogeneous AS modulate the formation of a sensorimotor circuit. Aim one will investigate the mechanism by which AS-encoded Sema3a protein polarizes motor neurons and its effects on motor neuron dendrite outgrowth. Aim two will study the effects of AS- encoded Sema3a in motor neuron circuit function, via additional training in slice electrophysiology. Aim three will determine the role of AS in guiding incoming sensory afferents that synapse on motor neurons through function of AS-encoded positional molecule EphA5. Together, these aims will greatly expand our understanding of the role of AS on the maturation of a defined monosynaptic CNS circuit. The training and mentorship proposed will prepare the candidate for an independent investigator position addressing the role of AS in neural circuit formation throughout the CNS. Ultimately, this strategy and training plan will open new avenues of research on glial-based treatments for neuropsychiatric disorders.

描述（由申请人提供）：星形胶质细胞（AS）是中枢神经系统中众多细胞，越来越多地被认为是神经发育和神经退行性疾病病理学的关键参与者，包括自闭症相关疾病RETT综合征和脆弱的X综合征，肌萎缩性的霉菌性孢子虫（Als）（Als）（Als）和Hounterton的疾病。该研究计划的目的是定义AS在指导功能神经回路形成中的作用。这位K08指导的临床科学家的申请人 研究职业发展奖是精神病学系的精神科医生和临床讲师，并且是加利福尼亚大学旧金山分校的David Rowitch博士的博士后研究员。该提案概述了一项为期4年的职业发展计划和研究策略，其中包括Rowitch博士，John Rubenstein博士和Erik Ullian博士的指导，以完成下面描述的研究目的。这些将使申请人能够实现跨越神经胶质生物学和神经精神病界面的独立实验室的职业目标。构成该提案基础的初步数据表明，指导分子Sema3a和Epha5是由腹侧唯一表达的，但不是背脊髓。从腹侧分泌的AS-编码SEMA3A对运动神经元位置，产后存活和突触发生的局部影响也是第一次被定义为异质性。研究策略将这些发现扩展在机械和功能方向上，以确定这些异质性如何调节感觉运动电路的形成。 AIM ONE将研究AS编码的SEMA3A蛋白偏振运动神经元及其对运动神经元树突生长的影响的机制。目标两个将通过SLICE电生理学进行其他训练，研究AS-SEMA3A在运动神经元电路功能中的影响。 AIM三将确定AS在引导传入的感觉传统中通过AS编码的位置分子以EPHA5的功能在运动神经元上突触的作用。总之，这些目标将大大扩展我们对定义单突触中心电路成熟的作用的理解。提出的培训和指导将为候选人做好准备的独立研究人员职位，以解决整个中枢神经系统中神经回路形成的作用。最终，该策略和培训计划将开辟有关神经精神疾病基于神经胶质治疗的研究的新途径。