Investigation of a candidate chemotherapy-induced nausea sensory circuit

描述(由申请人提供)：化疗引起的恶心对生活质量产生负面影响，可能改变对化疗治疗计划的遵守，并一再被开始癌症治疗的患者列为最大的恐惧。这个项目的目标是更好地了解感觉系统和分子机制，这些系统和分子机制涉及到检测导致恶心产生的刺激。我们希望定义一种分子上未被探索的感觉回路及其在调节生物行为和生理中的作用。最有效的抗恶心药物类靶向5-羟色胺受体优先表达于迷走神经的感觉成分。然而，这些纤维的神经支配的解剖分布仍然未知，操纵这一回路对行为的影响也是未知的。我将使用基因工具，包括小鼠转基因系和腺病毒载体基因传递，专门绘制解剖图，并从功能上操纵候选恶心回路。对这一系统的检查将开启对一个特征不佳和临床相关的感觉系统的基础研究，并为许多患者高度相关的治疗干预提供潜在的替代靶点。

DESCRIPTION (provided by applicant): Chemotherapy-induced nausea negatively impacts quality of life, can alter adherence to chemotherapeutic treatment plans, and is repeatedly ranked as the greatest fear by patients beginning cancer treatment. The goal of this project is to better understand the sensory systems and molecular mechanisms involved in detection of stimuli leading to generation of nausea. We hope to define a molecularly unexplored sensory circuit and its role in modulating organism behavior and physiology. The most efficacious anti-nausea medication class target serotonin receptors preferentially expressed in the sensory component of the vagus nerve. However, the anatomical distribution of innervation by these fibers remains unknown, as does the effect of manipulating this circuitry on behavior. I will use genetic tools including mouse transgenic lines and adenoviral vector gene delivery to specifically map the anatomy and functionally manipulate candidate nausea circuits. Examination of this system will open basic research into a poorly characterized and clinically relevant sensory system, and also provide potential alternative targets for therapeutic intervention of high relevance to many patients.