Genomics of Intracerebral Hemorrhage and its Causes

脑出血的基因组学及其病因

• 批准号: 10084327
• 负责人: Bradley Pearce Ander
• 金额: $ 59.57万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084327
• 关键词: 3-Dimensional; Accounting; Adverse effects; Affect; Alternative Splicing; Amyloid; Anti-Inflammatory Agents; Attenuated; Blood; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Platelets; Blood coagulation; Boston; Brain; Brain hemorrhage; CD14 gene; CD4 Positive T Lymphocytes; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Classification; Coagulation Process; Data; Dendritic Cells; Down-Regulation; Edema; Experimental Models; Extravasation; Fibroblast Growth Factor; Gene Expression; Genes; Genomics; Helper-Inducer T-Lymphocyte; Hematoma; Hemorrhage; Hour; Human; Hypertension; Hypertensive Intracerebral Hemorrhage; Immune; Immune response; Incidence; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Interleukin-10; Ischemic Stroke; Lesion; Leukocytes; Lobar; Lymphocyte; MMP9 gene; Measures; Messenger RNA; Microglia; Modeling; Molecular; Molecular Target; Mus; Outcome; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Population; RNA; Recurrence; Regulatory T-Lymphocyte; Resolution; Role; Severities; Structure; T cell regulation; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Transcript; Untranslated RNA; axon injury; base; brain repair; gene repair; improved; improved outcome; insight; ischemic lesion; macrophage; monocyte; mortality; neutrophil; peripheral blood; repaired; response; stroke patient; transcriptome sequencing; γδ T cells

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.

抽象的 脑出血（ICH）后，血脑屏障（BBB）被破坏 相关的水肿和白细胞从血液渗入组织/中性粒细胞， 单核细胞和淋巴细胞进入大脑，中性粒细胞增多或中性粒细胞向淋巴细胞增多。 人类的比率与较差的 ICH 结果相关，因此该提案将检查基因。 与缺血性卒中相比，ICH后中性粒细胞、单核细胞和T淋巴细胞中的表达 ICH 死亡率非常高，ICH 体积和水肿体积以及 ICH 的原因如下。 因此，该提案将检查中性粒细胞、单核细胞中的基因表达。 和T淋巴细胞作为ICH体积、水肿体积和ICH周围缺血性病变体积的函数， 以及 ICH 的原因，我们预计不同的 ICH 量会有不同的血液/白细胞/血小板特征。 以及影响血肿消退、复发性出血和复发严重程度的不同 ICH 原因 基于非常可靠的初步数据，出血将成为改善生存的分子目标。 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 和免疫相关的中性粒细胞、M1 单核细胞和特定 T 细胞亚群（γδT 细胞）； M2 单核细胞和特定 T 细胞亚群（例如 T 辅助细胞）中的修复基因稍后表达 ICH 后的时间（3 天、7 天）；并且显示基因和途径与缺血性中风的基因和途径不同。 目标#1b。证明血液中特定的 T 细胞和 T 细胞受体基因表达降低。 ICH 可能与血液 T 淋巴细胞数量减少相关（γδT 早期；T 辅助细胞、Tregs 目标#2。确定与 ICH 体积、水肿和相关的基因和通路。 考虑到不同大小的治疗差异后，随着时间的推移，ICH周围的缺血性病变 目标#3a。确定与高血压相关的深层 ICH 相关的特定基因和通路。 与根据修改后的波士顿标准 23-25 定义的可能的 CAA 相关的皮质脑叶 ICH 相比。 证明目标#3b，尽管存在一些与所有基因相关的共同基因和途径。 对于 ICH 的病因，每种病因都有大量特定的基因和通路。 因此，人类 ICH 的分子基础很大程度上尚未被探索。 将通过识别与因素相关的分子来开始增加我们对人类 ICH 的了解 与 ICH 结果相关（中性粒细胞、单核细胞、T 淋巴细胞以及 ICH 体积和 水肿量和 ICH 的原因）可能是改善 ICH 结果的治疗目标。