Novel Pathways in Ischemic Stroke in Sickle Cell Anemia

镰状细胞贫血症缺血性中风的新途径

基本信息

  • 批准号:
    10200126
  • 负责人:
  • 金额:
    $ 51.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Stroke is a devastating complication of sickle cell anemia (SCA) that will occur in ~11% of all patients without intervention. In pediatric patients with SCA, most of these strokes are ischemic and strongly linked with arterial vasculopathy. There is a strong heritable component that affects development of stroke in SCA patients. However, our understanding of the genes involved is very limited. Our group reported an unbiased genome wide association study of stroke in SCA using whole exome sequencing. We identified and validated two particular missense mutations in the GOLGB1 (Y1212C) and ENPP1 (K173Q) genes as being protective against stroke in SCA. Our study goal is to define the functional role of GOLGB1 and ENPP1 as modulators of vascular endothelial injury and ischemic stroke risk. We have previously observed that: a) GOLGB1 levels affect Golgi structure in monocytes and endothelial cells; b) The GOLGB1 Y1212C variant is associated with more dispersed Golgi in monocytes isolated from SCA patients; and c) ENPP1 enzymatic activity is higher in SCA patients with the protective K allele of the ENPP1 K173Q variant. From this preliminary data, we hypothesize that 1) GOLGB1 affects Golgi structure, which in turn regulates secretory output of pro-thrombotic factors such as von Willebrand factor (vWF) that can affect stroke in SCA; and 2) that ENPP1 affects risk of thrombosis either through endothelial cell signaling or by hydrolysis of the pro-inflammatory ATP inorganic pyrophosphate (PPi). We plan to test these hypotheses by analyzing the function of GOLGB1 and ENPP1 in samples from patients with SCA. We will isolate primary monocyte and endothelial cells from a large cohort of SCA patients receiving care at Texas Children’s Hospital.We will test our central hypotheses by pursuing three aims: Aim 1: Examine the role of GOLGB1 in the structure and function of Golgi complexes in sickle cell anemia - We will use high resolution imaging to determine the role of GOLGB1 in maintaining Golgi structure and protein trafficking in monocyte and endothelial cells from SCA patients; Aim 2: Determine the effect of ENPP1 activity in sickle cell anemia - We will measure plasma and endothelial activity of the ENPP1 enzyme.We will also test whether ENPP1 modulates vascular dysfunction in patients with SCA; Aim 3: Determine impact of GOLGB1 and ENPP1 on endothelial activation in a microfluidic arterial model - We will combine thrombotic protein assays and RNA expression profiling to identify endothelial activation pathways affected by our candidate genes. Our proposed studies will characterize the functional impact of our two genes and their genetic variants in SCA patient samples. This will benefit our understanding of the pathophysiological pathways of stroke and potentially provide targets for drug therapy to prevent or treat stroke in SCA patients.
卒中是镰状细胞性贫血(SCA)的一种破坏性并发症,在所有未发生中风的患者中,约11%会发生中风 干预。在患有SCA的儿童患者中,这些卒中大多是缺血性的,与动脉有很强的联系 血管病变。在SCA患者中,有一个很强的可遗传成分影响卒中的发展。 然而,我们对相关基因的了解非常有限。我们小组报告了一个没有偏见的全基因组 SCA卒中关联的全外显子测序研究。我们确定并验证了两个特定的 GOLGB1(Y1212C)和ENPP1(K173Q)基因错义突变对卒中的保护作用 SCA。我们的研究目标是确定GOLGB1和ENPP1作为血管内皮细胞调节因子的功能作用 损伤和缺血性中风风险。 我们先前观察到:a)GOLGB1水平影响单核细胞和内皮细胞的高尔基体结构 B)GOLGB1 Y1212C变异与SCA分离的单核细胞中更分散的高尔基体有关 C)具有ENPP1保护性K等位基因的SCA患者ENPP1酶活性较高 K173Q变种。根据这一初步数据,我们假设1)GOLGB1影响高尔基体结构,进而影响高尔基体结构 调节促血栓形成因子的分泌输出,如可影响中风的von Willebrand因子(VWF) 在SCA中;以及2)ENPP1通过内皮细胞信号转导或通过水解 促炎症的三磷酸腺苷无机焦磷酸(PPI)。我们计划通过分析 SCA患者外周血中GOLGB1和ENPP1的功能我们将分离原代单核细胞和 来自德克萨斯儿童医院接受护理的大量SCA患者的内皮细胞。我们将测试我们的 追求三个目标的中心假设:目标1:研究GOLGB1在结构和功能中的作用 镰状细胞性贫血的高尔基复合体-我们将使用高分辨率成像来确定GOLGB1在 维持SCA患者单核细胞和内皮细胞的高尔基体结构和蛋白质转运;目标2: 确定ENPP1活性在镰状细胞性贫血中的作用-我们将测定血浆和内皮细胞活性 我们还将测试ENPP1是否调节SCA患者的血管功能障碍;目的 3:在微流体动脉模型中确定GOLGB1和ENPP1对内皮激活的影响-我们将 结合血栓蛋白分析和RNA表达谱识别内皮细胞激活途径 受我们候选基因的影响。 我们提议的研究将表征我们的两个基因及其遗传变异对功能的影响 在SCA患者样本中。这将有助于我们了解中风和脑梗塞的病理生理机制。 有可能为预防或治疗SCA患者中风的药物治疗提供靶点。

项目成果

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Jonathan Michael Flanagan其他文献

Jonathan Michael Flanagan的其他文献

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{{ truncateString('Jonathan Michael Flanagan', 18)}}的其他基金

NOVEL PATHWAYS IN ISCHEMIC STROKE IN SICKLE CELL ANEMIA
镰状细胞性贫血缺血性中风的新途径
  • 批准号:
    9565807
  • 财政年份:
    2017
  • 资助金额:
    $ 51.6万
  • 项目类别:
Genetic Modifiers of Transfusional Iron Overload
输血铁超负荷的基因修饰
  • 批准号:
    9119096
  • 财政年份:
    2015
  • 资助金额:
    $ 51.6万
  • 项目类别:

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