Mechanisms of Dendrite Regeneration after Injury

在最直接的层面上，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。树突受创伤性脑损伤、中风和多种形式的神经变性的损伤，然而，尽管控制损伤后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。在哈佛大学约书亚·卡普兰博士的研究生培训期间，我使用了定量成像、行为和线虫遗传学来检查神经元回路发育的关键步骤。在加州大学旧金山分校跟随Yeh Nung Jan博士进行博士后培训期间，我已经过渡到研究果蝇神经元对树突损伤的反应。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能力，并正在利用这个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损伤的树突相同，就像感觉离子通道的运输和 细胞类型特异性转录因子的表达。然而，与未损伤的树突相比，损伤诱导的树突的形态和图案存在显着缺陷。此外，改变神经元兴奋性的操作专门改变了损伤后神经元的再生，而不影响未损伤的神经元，这表明树突再生是一个依赖活动的过程。我建议开发一个研究项目来加深我们对树突再生的了解，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更多的实验技能来测试再生的树突的功能。这些技能将促进这里提出的研究：调查树突再生的活性依赖性；检查再生树突形态及其功能变化背后的细胞生物学变化 结果：并探讨损伤后树突茎维持与树突再生的关系。拟议的实验培训和计划中的职业发展活动将为我过渡到作为研究机构终身教员领导独立和富有成效的研究项目做好准备。

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.