Novel approaches to neural regeneration: Defining new genes & pathways

神经再生的新方法：定义新基因

• 批准号: 7725773
• 负责人: Nancy M Bonini
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725773
• 关键词: Adult; Affect; Animal Model; Animals; Biological; Degenerative Disorder; Disease; Drosophila genus; Employee Strikes; Foundations; Genes; Injury; Lasers; Life; Natural regeneration; Nerve; Nerve Degeneration; Nerve Regeneration; Neurodegenerative Disorders; Neuronal Injury; Paralysed; Pathway interactions; Patients; Pilot Projects; Process; Quality of life; Speed; Spinal cord damage; Spinal cord injury; Staging; Stroke; System; Therapeutic; Traumatic Brain Injury; Wing; fly; insight; mature animal; mutant; nerve injury; novel strategies; novel therapeutics; public health relevance

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.

项目摘要 - 神经元损伤，例如脊髓损伤，是毁灭性的，通常会导致生活质量的极大降低。在美国，仅脊髓损伤就会影响约15,000人；这些患者中约有10,000名将永久瘫痪，许多其他患者因受伤而死亡。很少有方法可以治疗这种毁灭性的伤害，这在很大程度上是因为由于过程的复杂性和可用于攻击问题的有限系统，因此很少清楚影响再生的生物途径和基因。新的见解不仅适用于脊髓损伤，还适用于脑创伤，中风和神经退行性疾病。我们建议开发一种主要的模型生物系统 - 果蝇 - 作为成人神经再生的新实验范式。在活着的成年动物的试点研究中，我们用激光切断了机翼神经束，并观察到神经道的变性。引人注目的初步观察表明，经过3周的静止时期，神经束在约40％的动物中再生。我们将对这种神经损伤实验范式进行详细表征，包括变性的程度和速度，以及再生的速度，速度和准确性。然后，使用该系统，我们将利用果蝇中可用的分子定义基因突变体的可用集，以识别新的基因和途径。由于基线再生是部分的，因此该实验范式将揭示两种影响变性的途径，以及调节再生的途径。这些研究将建立一个用于再生研究的新实验范式，并揭示新的分子和途径，从而提供基本的生物学洞察力，并为发现新的治疗疗法的神经损伤，损伤和退化性疾病的基础。