A genetic screen for modulators of nociception

描述(由申请人提供)：我们的研究重点是揭示疼痛感知的分子机制。对疼痛刺激的感觉对有机体的生存至关重要。然而，由于受伤，急性和慢性疼痛影响着数亿人，是许多疾病的主要症状。不幸的是，目前可用的药物疗法具有许多有害的副作用和/或滥用和成瘾的可能性，同时在治疗持续性疼痛方面也不有效。尽管取得了很大的进步，但关于神经系统如何感知和编码痛苦或有害的刺激，仍有许多有待了解。在这里，我们建议使用斑马鱼系统进行正向遗传筛选，以阐明痛觉所需的神经回路的基本特性。我们已经开发了特定的转基因工具来检测特定神经元群体的发育和功能，这些群体检测到特定的伤害性刺激。我们建议使用这些工具来表征改变对热、冷、机械或化学刺激的行为反应的基因突变。我们的初步数据表明，我们可以识别影响不同疼痛模式的突变。我们希望这一基因筛查将为对神经回路和疼痛感知感兴趣的社区提供资源，并可能为虚弱疼痛条件的潜在治疗提供靶点。

DESCRIPTION (provided by applicant): Our research is focused on revealing the molecular mechanisms that underlie the perception of pain. Sensation of painful stimuli is critical for the survival of the organism. However, acute and chronic pain affects hundreds of millions of people as a result of injury, and is a major symptom in many illnesses. Unfortunately, currently available drug based therapies have numerous deleterious side effects and/or potential for abuse and addiction, while also not being effective in the treatment of persistent pain. Despite great advances, much remains to be understood about how painful or noxious stimuli are perceived and coded by the nervous system. Here we propose to use the zebrafish system to conduct a forward genetic screen to elucidate the fundamental properties of the neural circuits required for the sensation of pain. We have developed specific transgenic tools to examine the development and function of specific neuronal populations that detect modality specific nociceptive stimuli. We propose to use these tools to characterize genetic mutations that alter the behavioral response to heat, cold, mechanical or chemical irritants. Our preliminary data demonstrate that we can identify mutations affecting distinct pain modalities. We expect that this genetic screen will provide a resource for the community interested in the development of neural circuits and the perception of pain, and may provide targets for potential therapies for debilitating painful conditions.