Genomics of Intracerebral Hemorrhage and its Causes

摘要 脑出血(ICH)后，血脑屏障(BBB)被破坏 伴随的水肿和白细胞从血液中渗入组织/血肿。中性粒细胞， 单核细胞和淋巴细胞进入大脑。中性粒细胞增多或淋巴细胞中性粒细胞增多 人类的这一比例与较差的脑出血预后相关。因此，这项建议将检查基因 脑出血后中性粒细胞、单核细胞和T淋巴细胞的表达与缺血性卒中的比较 和控制。脑出血死亡率非常高，脑出血体积和水肿量以及脑出血的原因 生存的重要因素。因此，这项建议将检测中性粒细胞、单核细胞的基因表达。 T淋巴细胞对脑出血体积、脑水肿体积和脑出血周围缺血病变体积的影响。 以及脑出血的原因。我们预计不同的脑出血量会有不同的血液/白细胞/血小板图谱 不同的脑出血原因会影响血肿消退、复发出血和复发的严重程度 出血将成为提高存活率的分子靶点。基于非常可靠的初步数据 我们提出了以下目标。 目标#1a。证明促炎基因在早期(12h、1d、3d)表达 脑出血后中性粒细胞、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(如T辅助细胞)中的修复基因在稍后表达 脑出血后的时间(3d，7d)；以及，表明这些基因和途径与缺血性中风的不同。 目标#1b。表现出特定的T细胞，血液中T细胞受体基因的表达减少 ICH和这可能与血液中T淋巴细胞数量的减少(γδT早期；T辅助T，Treg 稍后)。目的#2.确定与脑出血体积、脑水肿和脑出血相关的基因和通路 脑出血周围缺血性病变随时间的变化，说明不同大小治疗后的差异 我也是。目标#3a。识别与高血压相关的深部脑出血相关的特定基因和途径 与修改的波士顿标准23-25所定义的与可能的CAA相关的皮质叶ICH相比。 目标#3b。证明了这一点，尽管有一些共同的基因和途径与ALL相关 对于脑出血的病因，有大量针对每种病因的特定基因和途径。 人类脑出血背后的分子基础在很大程度上还没有被探索。因此，这项提议 将开始通过识别与因子相关的分子来增加我们对人类脑出血的理解 与脑出血预后相关(中性粒细胞、单核细胞、T淋巴细胞以及脑出血体积和 水肿体积和脑出血的原因)，这些可能是改善脑出血预后的治疗目标。

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.