果蝇进食过程中的机械力调控

Mechanotransduction is the transformation of mechanical force to cell signaling. Mechanosensation, which underlies both hearing and somatosensation, is one of the least understood sensory modalities. It is thought to employ mechanosensitive (MS) ion channels to detect mechanical cues, such as touch, noxious mechanical stimuli, proprioceptive information and sound/vibration, however, the molecular and cellular mechanisms for mechanosensation remain largely unknown. Thus, identifying MS channels in mechanosensory neural circuits, and describing their physiological functions and gating mechanisms are the major foci of mechanotransduction studies. The fruit fly, Drosophila melanogaster, is an ideal model organism to investigate these questions on every level from the molecular to the behavioral. I propose to study this big-picture question (mechanosensation) with high-throughput approaches (fruit fly genetics and circuit mapping) and cutting-edge technologies., We found MS channels play essential roles in fly feeding. The mutant flies of piezo, a homolog for human MS channels piezo1 and piezo2, exhibit overconsumption behaviors over normal feeding conditions, indicating that enteric neurons fail to detect intestine stretch caused by food intake. We aim to decipher the molecular and circuitry mechanisms underlying this behavior. Our research will uncover the mechanosensory components of the “brain-gut-axis” regulation.

机械感受包括体表的触觉、机械痛以及体内的躯体姿态感觉与内脏感觉。机械感受由特异的离子通道和感觉神经元介导。机械力转导缺陷与许多临床疾病密切相关，相关研究对基础生物学和疾病的生物学基础研究都具有重要的意义。我们前期工作鉴定出了果蝇中负责触觉、本体感受和听觉的机械敏感离子通道和神经环路。在本项目中，我们计划以消化道中的机械力感受为研究系统，深入探讨机械感受调节内脏活动的分子与细胞机制和它的生理意义。我们发现机械敏感离子通道piezo突变的果蝇会过量进食，提示piezo参与感知与调控进食过程中消化道的体积和张力。深入了解胃肠道机械感受神经元的功能，不但可以帮助我们全面理解进食活动的调节机制，还可以应对由于体内机械感受紊乱引发的各种疾病。

进食是复杂而又受到精细调控的行为。消化道时刻处于动态调节过程，人体可以“感受”到消化道不同部位的机械信息，并对这些信息做出及时的反应。例如，当进食到一定阶段时，最先感受到由机械敏感神经元带来的饱胀感；而长时间未进食时，由于肠胃排空所激发的机械信息会带来迅速的饥饿感。然而，这些感受背后的神经机制尚不清楚。我们的研究发现，机械敏感离子通道基因piezo的突变（piezoKO）会显著影响果蝇的进食行为。与野生型相比，piezoKO果蝇会过量进食或者饮水，部分果蝇甚至会一直进食至嗉囊（功能与哺乳动物的胃相似）被胀破。我们进一步鉴定出果蝇脑中一群表达piezo的神经元，它们在果蝇嗉囊壁上形成丰富的树突结构，可以被嗉囊的胀大引起的张力激活，从而在进食过程中实时检测嗉囊的体积变化；失活这些神经元会导致过度进食，而激活它们可以抑制进食。我们还发现，小鼠或人的piezo1蛋白可以挽救果蝇piezo基因缺失导致的过量进食表型，提示机械力调节进食量这一功能在进化上可能是保守的（Neuron，2020）。以上研究揭示机械力对进食的影响是全面且显著的，并提示机械敏感离子通道是治疗进食紊乱的潜在靶点。