本体感觉调控的分子神经机制及其在发育和疾病中作用的研究

Proprioceptor and stretch-activated mechanosensitive ion channels play important roles in the function of the cardiovascular system and sensorimotor system. A number of TRP family channels have been implicated in cardiovascular diseases such as heart hypertrophy, defective vasomotor control and vasorelaxation, and cardiomyopathy. TRP family channels are highly conserved across phylogeny. The role of proprioceptors in regulating proprioception is also conserved. Thus, understanding the function and regulation of proprioceptors and TRP family channels in a genetic model organism will provide novel insights into their roles in human health and diseases particularly Stroke, Huntington’s disease, Parkinson’s disease and cardiovascular-related diseases. . We have reported the development of the nematode C. elegans as a genetic model organism for dissecting the role of proprioceptors and stretch-activated mechanosensitive channels in regulating proprioception. In this report, we have identified the first C. elegans proprioceptor DVA neuron that plays an important role in precise control of muscle contraction. We have found that a stretch-sensitive TRP channel TRP-4 acts in DVA to negatively regulate proprioception. Interestingly, we have also identified an unknown positive regulator that functions in DVA to promote muscle contraction. Thus, the DVA neuron, both positively and negatively modulates proprioception, providing a unique mechanism whereby a single proprioceptor neuron can fine-tune motor activity. Such a dual role for DVA is similar to that found for some human stretch receptors, indicative of functional conservation of proprioceptors in regulating proprioception between worms and humans. . Nevertheless, questions remain. For example, although my previous work has provided evidence that DVA neuron is a proprioceptor, the cellular mechanisms by which DVA regulates muscle activity are not known. The molecular identities of the positive regulator of DVA also remain mysterious. The current proposal is aimed to extend the above studies to elucidate the mechanisms by which the proprioceptor neuron DVA and the mechansensitive TRP-4 channel modulate proprioception. Our study will also offer an approach to identify key molecules involved in proprioception and study their function in development and related disease.

本体感受器和拉伸激活的机械敏感离子通道在感觉运动系统和心血管系统中起着重要的作用，了解本体感受器在遗传模式动物中的功能将对其在人类健康和疾病，特别是中风、亨廷顿舞蹈病、帕金森氏病和心血管相关疾病中的作用提供新见解。申请人首次发现线虫本体感受器DVA神经元，它在精确控制肌肉收缩方面起着重要作用。DVA中拉伸敏感的TRP-4通道在本体感觉中起负调节作用，同时未知的正调节因子在DVA中起作用。DVA可以正负调节本体感受，显示了由单一神经元精细调节运动的奇特机制。DVA的这种双重作用与人类牵张受体的作用类似，表明本体感受器在调节线虫和人类的本体感觉方面的功能保守性。但是DVA调节肌肉活动的细胞机制尚未知，其正调控因子也未鉴定。本项目拟在前期工作中建立的本体感受动物模型的基础上阐明本体感觉神经元DVA调节本体感受的关键分子调控网络以及它们在发育和相关疾病中的功能。

本体感受器和拉伸激活的机械敏感离子通道在感觉运动系统和心血管系统中起着重要的作用，了解本体感受器在遗传模式动物中的功能将对其在人类健康和疾病，特别是中风、亨廷顿 舞蹈病、帕金森氏病和心血管相关疾病中的作用提供新见解。申请人首次发现线虫本体感受器 DVA神经元，它在精确控制肌肉收缩方面起着重要作用。. 本项目中我们通过运动跟踪系统分析了本体感觉功能缺陷对线虫运动、摄食、寿命等功能的影响；利用秀丽线虫的遗传学优势，EMS诱变进行大规模modifier正向遗传筛选得到大量的突变体，对其中部分表型和功能明显的突变体进行了全基因组DNA测序和分析，寻找其中参与本体感觉正向调控的新基因；对已知机械敏感离子通道候选基因进行筛选，确认其中参与本体感觉调控的基因。利用新的10X单细胞测序技术，在线虫全身细胞中寻找更多线虫参与本体感觉调控的细胞以及本体感觉神经元的基因表达谱，同时该技术有利于我们寻找不同组织和细胞之间的调控关系。利用smart-seq单细胞测序技术研究衰老期间本体感觉细胞基因表达的变化，通过生物信息学分析建立基因调控网络。对大鼠本体感觉神经元生理和病理情况下分别进行drop-seq和10X单细胞测序及分析，在线虫本体感觉动物模型和哺乳动物之间搭建了本体感觉研究的桥梁。. 我们在全基因组范围内鉴定本体感觉的正调控因子，以及参与调节本体感觉的机械敏感离子通道、神经递质和神经肽; 厘清本体感觉神经元调控肌肉功能的分子调控网络和神经机制，可在基因、细胞和行为水平深入研究本体感觉分子调控机制，有助于进一步深入理解哺乳动物的本体感觉调控机制，为相关疾病的早期诊断和有效干预提供理论基础和崭新的手段，具有十分重要的科学意义。