Mechanism of memory decline after intra-ventricular hemorrhage

摘要 脑室内出血（IVH）和蛛网膜下腔出血（SAH） 出血（SAH）。认知缺陷通常包括顺行性和逆行性遗忘和缺陷 空间记忆功能受损，这说明海马体受损在我们的初步数据中， 开发了一种脑室内血液（IVB）和脑室内凝血酶（IVT）模型， 注射后5周，在Morris水迷宫范例中的表现显著变差 与假手术相比。在齿状回和海马区我们没有看到明显的神经元丢失 在这个时间点。然而，我们发现齿状核神经发生明显受损， 分裂祖细胞的数量大大减少，并且齿状祖细胞不能分化 转化成新的神经元src抑制剂PP 2可抑制IVT后的空间记忆障碍。这 这一发现使我们假设齿状突祖细胞的减少是由于凝血酶 通过蛋白酶激活受体1（PAR 1）激活SRC途径。补助金将检验这一点 假设并通过RNA测序鉴定信号级联的其他成员。我们 特别感兴趣的是将已知的齿状祖细胞维持的调节因子与 分化途径，如WNT-3A或音刺猬到我们的初步发现src途径 activation.该基金的目的是确定一个候选基因的管道，这些基因与基因组学有关。 移植诱导的齿状突祖细胞池的减少。候选基因的鉴定 将作为K 08期末R 01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， 出血或缺血以及他在全基因组转录组研究方面的经验。这笔赠款 这项提案旨在了解我们在研究之后看到的记忆功能障碍的基因组机制。 脑室内出血，以开发治疗这一重要临床问题的疗法。

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.