Region-restricted astrocytes in neural circuit formation and function

描述（由申请人提供）：星形胶质细胞（AS）是中枢神经系统中数量最多的细胞，并且越来越多地被认为是神经发育和神经退行性疾病病理学中的关键参与者，所述神经发育和神经退行性疾病包括自闭症相关病症Rett综合征和脆性X综合征、肌萎缩性侧索硬化症（ALS）和亨廷顿病.这项研究计划的目标是确定AS在指导功能神经回路形成中的作用。K08指导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病学家和临床导师，也是加州大学弗朗西斯科分校大卫Rowitch博士的博士后研究员。该提案概述了一个为期4年的职业发展计划和研究战略，其中包括博士的指导。总之，这些将使申请人能够实现经营一个独立的实验室跨越神经胶质生物学和神经精神疾病的接口的职业目标。初步的数据，形成了这个建议的基础表明，指导分子Sema3a和EphA5是唯一的腹侧，但不是背侧脊髓AS表达。腹侧AS分泌的AS编码的Sema3a对运动神经元位置、出生后存活和突触发生具有局部影响，首次证明了分子定义的AS异质性。研究策略扩展这些发现的机制和功能的方向，以确定这些异构AS调制的感觉运动电路的形成。目的研究AS编码的Sema3a蛋白对运动神经元的极化机制及其对运动神经元树突生长的影响。目的二通过切片电生理学的附加训练，研究AS编码的Sema3a对运动神经元电路功能的影响。目的三：通过AS编码的定位分子EphA5的功能，确定AS在引导传入感觉传入神经元与运动神经元突触中的作用。总之，这些目标将大大扩大我们的理解AS的作用成熟的一个明确的单突触中枢神经系统电路。建议的培训和指导将准备候选人的一个独立的调查员的位置解决的作用，AS在整个中枢神经系统的神经回路形成。最终，这一策略和培训计划将为神经精神疾病的神经胶质治疗开辟新的研究途径。

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.