申请人为教授、博士生导师，首批“浙江大学求是青年学者”，获Servier青年药理学工作者奖。主要从事缺血性脑损伤的发病机制及药物靶标研究，发现在缺血性脑损伤中组胺及其受体具有多靶点多环节的调控作用，并且酸后处理可以通过上调线粒体自噬发挥保护作用。以上结果为缺血性脑损伤的防治提供重要的药物新靶标，因此受邀为Pharmacol Therapeut撰写综述，并获省自然科学一等奖。曾获4项国家基金和省杰青，发表SCI论文48篇（总IF为231，被引821次），包括在Nat Commun、Autophagy、Brain Behav Immun、Biomaterials等期刊发表第一或通讯作者论文26篇，申请发明专利两项。申请人拟利用H3受体条件性基因敲除小鼠及活体成像技术等，阐明组胺H3受体在脑缺血后血管再生中的作用及机制，为H3受体拮抗剂临床用于脑缺血治疗、发挥精准神经保护作用提供理论依据。

The applicant is a professor and Ph.D. supervisor of pharmacology department of Zhejiang University. She has obtained the first Qiushi Young Scholarship of Zhejiang University and Servier Young Investigator Award. Her main research interests focus on the study of the pathological mechanism of cerebral ischemia and searching related drug targets. Her studies demonstrate that histamine and its H1, H2 and H3 receptors participate in ischemic brain injury by targeting both neurons and glia at the different stages following ischemia. Moreover, acidic postconditioning by carbon dioxide inhalation protects against ischemic brain injury through PARK2-dependent mitophagy. The aforementioned investigations provide more therapeutic targets and strategies for the treatment of ischemic brain injury. Based on previous studies, the applicant has published a review in Pharmacol Therapeut (2017) and achieved the first prize of Zhejiang Provincial Natural Science Award (2/5) in 2015. She has also obtained four projects from National Natural Science Foundation of China, one Science Fund for Distinguished Young Scholars from Zhejiang Province and two national patents for invention and published 48 SCI-included papers (total impact factor: 231). Twenty-six among them were published as the first or corresponding author, including the publications in Nat Commun, Autophagy, Brain Behav Immun, Biomaterials and J Cereb Blood Flow Metab. The present project will investigate the role of histamine H3 receptors in angiogenesis following cerebral ischemia by employing H3 receptor conditional knockout mice and real-time microscopy. It will provide therapeutic targets for ischemic brain injury, and H3 receptor antagonists may have potential value in the recovery of ischemic brain injury.

在前期利用基因芯片分析的基础上，围绕脆性X 综合症小鼠脑内mRNA 表达异常的基因，两年来关注Caveolin-1、Granulin、DDO（D-Serine代谢酶）和褪黑素等调节雌激素，以及GABAA 受体、mGluR、NMDA受体介导的突触传递和兴奋/抑制平衡作用。在本研究中，发现雌二醇（E2）诱导神经元AMPA受体GluA1膜表面表达和磷酸化在FMR1基因敲除小鼠出现异常。此外，E2介导的促进长时程增强（LTP）和恐惧记忆在FMR1基因敲除小鼠的前扣带皮层也显著受损。分子机制研究发现小窝蛋白Caveolin-1（CAV1）和膜雌激素受体ERα的耦合在FMR1基因敲除小鼠明显增加，这可能是导致E2信号系统异常的主要原因。应用增加shRNA特异性降低CAV1表达，可以恢复E2诱导神经元AMPA受体GluA1膜表面表达和磷酸化作用；并有效改善FMR1基因敲除小鼠学习与记忆行为。Progranulin（PGRN）由GRN基因编码，为Granulin的前体，是一个关键的中枢抗炎因子和神经营养因子。我们的研究发现，脆性X综合征（FXS）即FMR1基因敲除小鼠由于脆性X智力低下蛋白FMRP的损失，影响RNA翻译和运输。我们发现FMR1基因敲除小鼠（KO小鼠）PGRN水平显著升高，利用shRNA降低PGRN可显著改善前扣带回皮层突触可塑性（LTP），并改善神经元树突发育及小鼠行为学表现包括痕迹恐惧记忆障碍和多动症。相关研究工作已在Annals of Neurology (IF=11.91)，Brain (IF=10.292)，Psychoneuroendocrinology (IF=5.591)等杂志发表。共计发表SCI论文29篇。2016年获陕西省科学技术一等奖（第一）。