Mechanisms of Dendrite Regeneration after Injury

损伤后树突再生的机制

• 批准号: 10213145
• 负责人: Katherine Louise Thompson-Peer
• 金额: $ 24.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213145
• 关键词: Actins; Affect; Afferent Neurons; Antibodies; Axon; Behavior; Biological; Caenorhabditis elegans; Calcium; Calcium Signaling; Caliber; Cells; Characteristics; Cytoskeleton; Defect; Dendrite Regeneration; Dendrites; Dependence; Detection; Development; Disease model; Drosophila genus; Electrophysiology (science); Elements; Embryo; Exhibits; Faculty; Failure; Genetic; Goals; Growth; Injury; Institution; Ion Channel; Knowledge; Larva; Learning; Light; Maintenance; Membrane Potentials; Mentors; Microtubules; Monitor; Morphology; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Pattern; Peripheral Nervous System; Phase; Play; Process; Pupa; Reporter; Research; Role; Sensory; Signal Pathway; Signal Transduction; Stimulus; Stroke; Synapses; System; Testing; Touch sensation; Training; Transgenes; Traumatic Brain Injury; axon regeneration; base; career development; cell type; clinically relevant; experimental study; follow-up; injured; juvenile animal; mature animal; member; mutant; neuron loss; neuronal cell body; neuronal circuitry; optogenetics; post-doctoral training; prevent; programs; quantitative imaging; receptive field; response; sensory stimulus; skills; tenure track; tool; trafficking; transcription factor; voltage

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.

在最简单的层面上，神经元通过树突接收信息，并通过轴突将信息传递给突触。创伤性脑损伤、中风和许多形式的神经退行性疾病都会损伤树突，然而，尽管对损伤后控制轴突再生的因素已经进行了广泛的研究，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。在哈佛大学跟随Joshua Kaplan博士进行研究生培训期间，我使用定量成像、行为学和秀丽隐杆线虫遗传学来研究神经元回路发育的关键步骤。在加州大学旧金山分校跟随Yuh Nung Jan博士进行博士后培训时，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，我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和未受伤的树突在很多方面都是一样的，比如感觉离子通道的传输和