Novel approaches to neural regeneration: Defining new genes & pathways

项目摘要-神经损伤，如脊髓损伤，是毁灭性的，通常会导致生活质量的极大降低。在美国，仅脊髓损伤每年就影响约15,000人；这些患者中大约有1万人将永久瘫痪，还有许多人因受伤而死亡。治疗这种毁灭性损伤的方法很少，很大程度上是因为影响再生的生物途径和基因尚不清楚，这是由于再生过程的复杂性和可用的解决问题的系统有限。新的见解可能不仅适用于脊髓损伤，也适用于脑外伤、中风和神经退行性疾病。我们建议开发一个主要的模式生物系统-果蝇-作为成人阶段神经再生的新实验范例。在活体成年动物的初步研究中，我们用激光切断了翅膀的神经束，观察到神经束的退化。令人震惊的初步观察表明，经过3周的静止期后，大约40%的动物的神经束再生。我们将详细描述这种神经损伤实验模式，包括退行性变的程度和速度，以及再生的程度、速度和准确性。然后，利用该系统，我们将利用苍蝇中可用的分子定义基因突变集来识别新的基因和途径。因为基线再生似乎是局部的，这个实验范式将揭示影响退化的两种途径，以及调节再生的途径。这些研究将为再生研究建立新的实验范式，揭示新的分子和途径，为发现神经损伤、损伤和退行性疾病的新疗法提供基本的生物学见解和基础。

Project Summary - Neuronal injury, such as spinal cord damage, is devastating and typically leads to extreme reduction in life quality. Spinal cord injuries alone affect ~15,000 people/year in the US; about 10,000 of these patients will be permanently paralyzed and many others die due to their injuries. Few approaches are available to treat such devastating injuries, in large part because little is clear about biological pathways & genes that influence regeneration, due to the complexity of the process and the limited systems available for attacking the problem. New insight may be applicable not only to spinal cord injury, but also to brain trauma, stroke and neurodegenerative disease. We propose to develop one of the premier model organism systems-Drosophila-as a new experimental paradigm for adult-stage neural regeneration. In pilot studies in living adult animals, we have severed the wing nerve bundle with a laser and observed degeneration of the nerve tract. Striking preliminary observations show that after a 3-week quiescent period, the nerve bundle regenerates in about 40% of the animals. We will perform detailed characterization of this nerve injury experimental paradigm, including extent and speed of degeneration, as well as extent, speed and accuracy of regeneration. Then, using this system, we will exploit the available sets of molecularly-defined gene mutants in the fly to identify new genes & pathways. Because the baseline regeneration appears partial, this experimental paradigm will reveal both pathways that influence degeneration, as well as those that modulate regeneration. These studies will establish a new experimental paradigm for regeneration studies, and reveal new molecules & pathways, providing basic biological insight and the foundation for discovery of novel therapeutics for nerve injury, damage and degenerative disease.