神经元中的Pen-2缺失诱导脑微出血及其机制研究

脑微出血是脑小血管病常见的一种脑磁共振表现（MRI/SWI序列上可见低信号病灶），可介导脑出血、认知功能障碍和脑梗死等，由于机制不清而无治疗方法。我们的前期研究发现，神经元内缺失Pen-2可发生脑微出血。其可能机制与抑制Notch1蛋白胞内结构域的生成，导致血管结构异常有关。本研究拟采用条件性敲除神经元内Pen-2的小鼠，并通过病理学、生化与分子生物学、细胞生物学等技术，1）明确Pen-2缺失和脑微出血发生发展相关；2）阐明Pen-2缺失可致血管结构异常是微出血的解剖基础；3）揭示Pen-2激活Notch1通路及其相关下游靶点可能是脑微出血发生的机制。本研究成果提出了脑微出血的新机制，为靶向Pen-2，研发微出血干预措施提供理论依据。

Cerebral microbleed is a common brain magnetic resonance manifestation of cerebral small vascular diseases (low signal lesions on MRI/SWI sequence), which can mediate cerebral hemorrhage, cognitive dysfunction and cerebral infarction. There is no treatment because the mechanism is unclear. Our previous study found that loss of Pen-2 in neurons can lead to cerebral microbleeds. The possible mechanism is related to the inhibition of the intracellular domain of Notch1 protein, leading to vascular structural abnormalities. In this study, we use conditional knockout mice in which Pen-2 is specifically inactivated in neurons. We aim to: 1) confirm the correlation between Pen-2 deletion and the occurrence of cerebral microbleeds; 2) elucidate that the abnormal vascular structure caused by Pen-2 deletion is the anatomical basis of microbleeds; 3) reveal that the activation of Notch1 pathway and downstream targets by Pen-2 may be the mechanism of cerebral microbleeds. The results of this study are expected to propose a new mechanism of cerebral microbleeds and provide a theoretical basis for its treatment and drug development targeting Pen-2.