Mechanism of memory decline after intra-ventricular hemorrhage

摘要 脑室出血(IVH)和蛛网膜下腔出血后常见的智能障碍 出血(SAH)。认知缺陷通常包括顺行性和逆行性健忘症和缺陷 在空间记忆功能方面，这指向海马区的损伤。在我们的初步数据中，我们有 开发了一种脑室内血液(IVB)和脑室内凝血酶(IVT)的模型，它可以产生 注射后5周Morris水迷宫测试成绩明显下降 与假手术相比。我们没有在齿状回或海马区看到明显的神经元丢失。 在这个时间点。然而，我们看到齿状神经发生的显著损害，这一点得到了证实。 极大地减少了分裂祖细胞的数量，并使齿状祖细胞无法分化 转化成新的神经元。Src抑制剂PP2可抑制IVT后的空间记忆障碍。这 这一发现使我们产生了一种假设，即齿状祖细胞减少是由于凝血酶 通过蛋白酶激活受体1(Par1)激活src通路。这笔拨款将检验这一点 假设，并通过RNA测序确定信号级联的更多成员。我们是 特别感兴趣的是将已知的齿状祖细胞维持和调节因子联系起来 WNT-3A或Sonic Hedgehog等分化途径对我们初步发现src途径的影响 激活。这项拨款的目的是确定一系列候选基因，这些基因与 失血引起的齿状祖细胞库的减少。候选基因的鉴定 将作为K08期间结束时R01申请的基础。我的导师弗兰克 夏普是这个项目的理想人选，因为他在齿状神经发生方面有丰富的经验 出血或缺血以及他的全基因组转录组研究经验。这笔赠款 该提案旨在了解我们在之后看到的记忆障碍的基因组机制 开发治疗脑室出血的方法来治疗这一重要的临床问题。

Abstract Intellectual deficits are common following intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Cognitive deficits often include anterograde and retrograde amnesia and deficits in spatial memory function which points towards hippocampal injury. In our preliminary data, we have developed a model of intraventricular blood (IVB) and intraventricular thrombin (IVT) which produces a significantly worse performance in the Morris water maze paradigm 5 weeks after the injection compared to sham surgery. We did not see obvious neuronal loss in the dentate gyrus or hippocampus at this time point. However, we saw a significant impairment in dentate neurogenesis as evidenced by vastly reduced numbers of dividing progenitor cells and failure of dentate progenitor cells to differentiate into new neurons. Spatial memory deficits after IVT could be inhibited by the src inhibitor PP2. This finding has led us to the hypothesis that the decrease in dentate progenitor cells is due to thrombin activation of the src pathway through protease-activated receptor 1 (PAR1). The grant will test this hypothesis and identify further members of the signaling cascade with RNA sequencing. We are especially interested in linking known regulators of the dentate progenitor cell maintenance and differentiation pathways such as WNT-3A or sonic hedgehog to our preliminary finding of src pathway activation. The grant is aimed to identify a pipeline of candidate genes which are implicated in the hemorrhage-induced decline of the pool of dentate progenitor cells. Identification of candidate genes will serve as the basis for an R01 application towards the end of the K08 period. My mentor Frank Sharp is ideal for this project due to his extensive experience with dentate neurogenesis in the setting of hemorrhage or ischemia as well as his experience with whole-genome transcriptome studies. This grant proposal is aimed to understand the genomic mechanism of memory dysfunction that we see after intraventricular hemorrhage to develop therapies to treat this important clinical problem.