申请人长期从事神经生理及疾病研究，取得一系列开创性成果：1）揭示了神经兴奋性这一神经元最根本性质的维持和调控的关键分子，背景钠通道NALCN；2）提出并证实了利用遗传学筛选发现致病蛋白水平调控基因作为药靶的药物研发新思路，并揭示了神经退行性疾病亨廷顿病的潜在药靶基因NUB1，为此类疾病干预带来希望。以第一或通讯作者在Nature、Cell、Neuron、Nature Neuroscience等期刊发表论文7篇，总影响因子122，篇均17，单篇他引逾100次，多次被Nature Reviews Neuroscience等期刊专文评论。任Frontiers in Bioscience编委及Journal of Neuroscience审稿人。获首届吴瑞基金会“顾孝诚奖”（PI奖，全国共2人）、科技部“863“青年科学家、中组部”青年千人“。申请人拟研究筛选所得激酶对亨廷顿病的作用机制。

The applicant has made a number of original discoveries in the neuroscience field, focusing on the molecular mechanisms of both neurophysiology and neurodegenerative diseases. The major contributions include: 1) Revealed the molecular identity of the background sodium channel NALCN, which is the key player of neuronal excitability control at the baseline levels as well as its regulation by neuropeptides and extracellular calcium; 2) Established the “proof of concept” screening for genetic modifiers of mutant HTT protein, which causes the neurodegenerative Huntington’s disease, and identified a number of modifiers of mutant HTT levels and toxicity as potential therapeutic targets for the neurodegenerative Huntington's disease. The work has been published as original research articles in "Nature"," Cell", "Nature Neuroscience", "Neuron", etc., with the applicant being the first and/or corresponding authors. The total impact factor is about 122, and a single article has been cited over 100 times. The work has been recommended by top neuroscientists in full length comment/review/preview/editorial articles in "Nature Reviews Neuroscience", "Nature Neuroscience", "Neuron", "EMBO Journal", "Science Signaling", "Faculty of 1000", etc. The applicant has received recognitions for his work by many requests for collaboration and meeting invitations, as well as a number of awards such as the Ray Wu memorial fund award for principle investigators (the first "Gu Xiaocheng Lecturer" award), the “863 young scientist” of the Ministry of Science and Technology, the national “young 1000 talent”, etc. In addition, the applicant has been invited to be an editorial board member/managing editor of international journals such as "Frontiers in Bioscience", and to be an ad hoc reviewer for the well known journals such as "The Journal of Neuroscience". The applicant plans to further pursue the mechanistic study of the kinases that were identified from the screens.

神经退行性疾病引起中枢神经系统特定神经元不正常死亡萎缩，导致神经功能严重缺陷，认知或运动功能障碍，是最重要的神经疾病之一。目前此类疾病尚没有可以改变疾病进程的根本性治疗方法。是神经退行性疾病中最主要的单基因遗传病。由于其遗传图景清晰，是此类疾病重要的模式疾病。遗传学证据表明，HD主要由突变基因HTT所表达的突变HTT蛋白的神经毒性所导致，因此HTT蛋白如何调控以及如何降低HTT蛋白水平至关重要，并且可能为疾病治疗提供重要药靶。我们在病人细胞中发现两个激酶基因MAPK11及HIPK3可以对mHTT的聚集水平进行正反馈调控。在多种HD细胞模型及动物模型中，敲减或敲除MAPK11或者HIPK3均能显著降低mHTT的水平，但在野生型细胞中，这种效应并不存在。我们的进一步研究发现，MAPK11和HIPK3对HTT蛋白的调控依赖于mHTT的存在，这是因为变异mHTT可激活或增加MAPK11和HIPK3，这样形成了正反馈循环，加速了mHTT的积累与聚集，并由此参与了疾病的发生发展。我们还研究了MAPK11和HIPK3作为亨廷顿病药靶的潜在可能性，证明敲除MAPK11或HIPK3均能显著降低mHTT的水平，阻止mHTT的聚集，有效挽救/缓解病人干细胞分化的HD神经元的死亡以及HD小鼠中由疾病引起的运动能力障碍。 以上研究揭示了mHTT异常聚集的正反馈机制，提出这是导致疾病发展加剧的重要原因。我们还提出抑制mHTT异常积累聚集的潜在靶标，即MAPK11及HIPK3，并通过其已知的小分子化合物进行了验证。 项目相关通讯作者论文已发表于Cell Research、Nature Chemical Biology、Journal of Huntington’s Disease等期刊。