Mechanisms of Dendrite Regeneration after Injury

在最简单的层次上，神经元沿着树突接收信息，并将信息沿着轴突发送到突触接触点。树突被创伤性脑损伤、中风和许多形式的神经变性所损伤，然而，虽然损伤后控制轴突再生的因素已经被广泛研究，但我们对树突再生几乎一无所知。我的长期研究目标是了解损伤后树突再生的细胞机制。在哈佛，我和约书亚·卡普兰博士一起接受研究生培训时，我使用了定量成像、行为和C。elegans遗传学来研究神经回路发育的关键步骤。在加州大学旧金山分校的Yuh Nung Jan博士的博士后培训中，我已经过渡到研究果蝇树突损伤对神经元的反应。我发现果蝇周围神经系统中的DA感觉神经元在损伤后表现出强大的树突再生，并使用该系统来探索树突再生的基本特征。我观察到再生的树突在许多方面与未受伤的树突相同，如感觉离子通道的运输和神经元的再生。 细胞类型特异性转录因子的表达。然而，损伤诱导的树突的形态和图案相比，未受伤的树突显着缺陷。此外，操纵，改变神经元的兴奋性，特别是改变损伤后的神经元的再生，而不影响未受伤的神经元，这表明树突再生是一个活动依赖性的过程。我建议发展一个研究项目来加深我们对树突再生的认识，这将为理解神经元如何从损伤中恢复创造一个新的框架。我在K99指导阶段的短期研究目标是获得额外的实验技能，以测试再生树突的功能。这些技术将有助于研究：研究树突再生的活性依赖性;检查细胞生物学变化，这些变化是再生树突形态及其功能改变的基础。 结果;并探讨损伤后树突乔木维持和树突再生之间的关系。拟议的实验培训和计划中的职业发展活动将使我准备过渡到领导一个独立的和富有成效的研究计划作为终身教职员工在一个研究机构。

At the most straightforward level, a neuron receives information along dendrites, and sends information down an axon to synaptic contacts. Dendrites are injured by traumatic brain injury, stroke, and many forms of neurodegeneration, yet while factors that control axon regeneration after injury have been extensively studied, we know almost nothing about dendrite regeneration. My long term research goal is to understand the cellular mechanisms of dendrite regeneration after injury. During my graduate training with Dr Joshua Kaplan at Harvard, I used quantitative imaging, behavior, and C. elegans genetics to examine a key step in neuronal circuit development. For my postdoctoral training with Dr Yuh Nung Jan at UCSF, I have transitioned to studying the response to neurons to dendrite injury in Drosophila. I have found that the da sensory neurons in the Drosophila peripheral nervous system exhibit robust regeneration of dendrites after injury and am using this system to explore fundamental features of dendrite regeneration. I have observed that regenerated dendrites are identical to uninjured dendrites in many ways, like the trafficking of sensory ion channels and the expression of cell-type specific transcription factors. However the morphology and patterning of injury-induced dendrites are significantly defective compared to uninjured dendrites. Moreover, manipulations that alter the excitability of neurons specifically alter the regrowth of neurons after injury without affecting uninjured neurons, suggesting that dendrite regeneration is an activity-dependent process. I propose that developing a research program to deepen our knowledge about dendrite regeneration will create a new framework for understanding how neurons recover from injury. My short term research goals for the K99 mentored phase are to gain additional experimental skills to test the function of regenerated dendrites. These skills will facilitate the research proposed here: to investigate the activity dependence of dendrite regeneration; to examine the cell biological changes that underlie the alterations in regenerated dendrite morphology and their functional consequences; and explore the relationship between dendrite arbor maintenance and dendrite regeneration after injury. The proposed experimental training and the planned career development activities will prepare me to transition to leading an independent and productive research program as a tenure-track faculty member at a research institution.