Genomics of Intracerebral Hemorrhage and its Causes

摘要 脑出血（ICH）后，血脑屏障（BBB）被破坏， 相关水肿和白细胞从血液外渗到组织/血肿中。中性粒细胞， 单核细胞和淋巴细胞进入大脑。中性粒细胞增加或中性粒细胞-淋巴细胞比例增加 在人类中的比例与更差的ICH结局相关。因此，该建议将检查基因 与缺血性卒中相比，ICH后中性粒细胞、单核细胞和T淋巴细胞的表达 和控制。脑出血死亡率非常高，脑出血体积和水肿体积以及脑出血的原因是 生存的重要因素。因此，该建议将检查中性粒细胞、单核细胞 T淋巴细胞与脑出血体积、脑水肿体积和脑出血周围缺血灶体积的关系， 以及ICH的原因。我们预期不同ICH体积的血液/白细胞/血小板特征不同 以及影响血肿消退、复发性出血和复发性出血严重程度的不同ICH原因。 出血是提高存活率的分子靶点。基于非常可靠的初步数据 我们提出以下目标。 目标1a。证明促炎基因在早期（12小时，1天，3天）表达， ICH后中性粒细胞、M1单核细胞和特异性T细胞亚群（γδT细胞）;以及免疫相关 M2单核细胞和特定T细胞亚群（例如T辅助细胞）中的修复基因在较晚的时间表达。 时间（3d，7 d）;和，显示基因和途径不同于缺血性卒中。 目标1b。证明血液中特异性T细胞和T细胞受体基因表达降低， 这可能与血液T淋巴细胞（γδT早期; T辅助细胞，T淋巴细胞）数量减少有关。 稍后）。目标2。确定与脑出血体积、水肿和出血相关的基因和途径。 脑出血周围缺血性病灶随时间的变化，经不同大小的处理后有差异 ICH。目标3a。确定与高血压相关的深部ICH相关的特定基因和途径 与经修订的波士顿标准定义的可能与CAA相关的皮质叶ICH相比23 -25。 目标3b。证明，虽然有一些共同的基因和途径与所有 脑出血的原因，有大量的基因和途径，是具体的每一个原因。 人类ICH的分子基础在很大程度上尚未探索。因此，本提案 我们将开始通过鉴定与脑出血相关的分子， 与ICH结局相关（中性粒细胞、单核细胞、T淋巴细胞以及ICH体积和 水肿体积和ICH的原因），可能是改善ICH结局的治疗目标。

Abstract Following Intracerebral Hemorrhage (ICH), the blood–brain barrier (BBB) is disrupted with associated edema and leukocyte extravasation from blood into the tissue/hematoma. Neutrophils, monocytes and lymphocytes enter brain. Increased neutrophils or increased neutrophil to lymphocyte ratio in humans are associated with worse ICH outcomes. Thus this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes following ICH as compared to ischemic stroke and controls. ICH mortality is very high, with ICH volumes and edema volumes and causes of ICH being important factors in survival. Thus, this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes as function of ICH volume, edema volume and ischemic lesion volume around ICH, as well as causes of ICH. We expect different blood/ leukocyte/ platelet profiles for different ICH volumes and different ICH causes that affect hematoma resolution, recurrent bleeding, and severity of recurrent bleeding that would be molecular targets for improving survival. Based upon very robust preliminary data we propose the following aims. Aim #1a. Demonstrate that proinflammatory genes are expressed at early times (12h, 1d, 3d) in neutrophils, M1 monocytes and specific T cell subsets (γδT cells) following ICH; and immune-related repair genes in M2 monocytes and specific T cell subsets (e.g. T helper cells) are expressed at later times following ICH (3d, 7d); and, show the genes and pathways differ from those for ischemic stroke. Aim #1b. Demonstrate specific T cell, and T-cell receptor gene expression decreases in blood following ICH and this may correlate with decreased numbers of blood T lymphocytes (γδT early; T helper, Tregs later). Aim #2. Determine the genes and pathways that correlate with volume of ICH, edema and ischemic lesions around ICH over time, after accounting for differences in treatment for different sized ICH. Aim #3a. Identify specific genes and pathways associated with deep ICH related to hypertension compared to cortical lobar ICH related to probable CAA as defined by the modified Boston Criteria23-25. Aim #3b. Demonstrate that, though there are some common genes and pathways associated with all causes of ICH, there are large numbers of genes and pathways that are specific for each cause. The molecular underpinnings underlying human ICH are largely unexplored. Thus, this proposal will begin to increase our understanding of human ICH by identifying molecules that correlate with factors associated with ICH outcomes (neutrophils, monocytes, T lymphocytes, as well as ICH volumes and edema volumes, and causes of ICH) that might be treatment targets to improve ICH outcomes.