REGULATION OF SICKLE CELL PHOSPHOLIPID ORGANIZATION

暴露红细胞的磷脂酰丝氨酸（PS）的存在与以下疾病的病理生理学有关： 镰状细胞病（SCD），包括止血失衡、卒中风险、红细胞增多 内皮相互作用和血管损伤。我们的长期目标是了解 导致红细胞磷脂不对称性丧失和PS暴露的机制 膜，为什么这些细胞在SCD中以如此高的水平存在，以及它们如何导致 SCD病理学。我们假设一个新的事件链，其中（炎症）脂质 介质触发信号转导途径，导致PS暴露在红细胞表面。 此外，这些脂质介质可能会影响细胞间的相互作用。为了解决动态问题， 机制，将导致PS暴露和影响红细胞内皮细胞的相互作用，我们有 制定了以下具体目标：一。评估SCD中炎性脂质介质的增加对亚群中磷脂不对称性丧失的影响 镰刀形细胞二.探讨红细胞内信号通路在糖尿病肾病中的作用。 flipase和scramblase的调节，和三.为了研究改变的 红细胞脂质对循环中细胞-细胞相互作用和生理过程的影响。到 为了实现这些目标，我们将使用多学科的方法，利用生物化学和细胞 生物学技术在明确定义的条件下研究红细胞和内皮细胞。我们 将使用SCD患者的血液样本以及SCD的转基因小鼠模型。我们将 测量体内脂质介质如LPA的存在，测量体内LPA的产生， 体外并确定其作用。我们将把体外研究的数据与SCD的体内结果联系起来 血管闭塞危象、中风和急性胸部综合征患者，以及我们的小鼠 SCD的模型。总之，我们的结果可能表明新的治疗方案， SCD的管理。

The presence of phosphatidylserine (PS) exposing red cells is linked to the pathophysiology of sickle cell disease (SCD), including imbalance in hemostasis, risk for stroke, increased red cell endothelial interaction and vascular damage. Our long term goal is to understand the mechanisms that lead to the loss of phospholipid asymmetry and the exposure of PS in red cell membranes, why these cells are present at such a high level in SCD, and how they result in SCD pathology. We hypothesize a novel chain of events in which (inflammatory) lipid mediators trigger signal transduction pathways leading to PS exposure on the red cell surface. In addition, these lipid mediators may influence cell-cell interaction. To address the dynamic mechanisms that will lead to PS exposure and affect red cell endothelial interaction, we have developed the following specific aims: I. To assess the influence of the increased presence of inflammatory lipid mediators in SCD on the loss of phospholipid asymmetry in subpopulations of sickle ceils. II. To investigate the role of intracellular signaling pathways in the erythrocyte in the regulation of the flipase and the scramblase., and III. To investigate the role of altered erythrocyte lipids on cell-cell interaction and physiological processes in the circulation. To accomplish these goals, we will use a multidisciplinary approach using biochemistry and cell biology techniques to study red cells and endothelial cells under well-defined conditions. We will use blood samples from SCD patients as well as a transgenic mouse model for SCD. We will measure the presence of lipid mediators such as LPA in vivo, measure the generation of LPA in vitro and define its role. We will relate the data of in vitro studies to in vivo findings in SCD patients with vaso-occlusive crisis, stroke and acute chest syndrome, as well as in our murine model for SCD. Together, our results may indicate novel treatment regimens in the management of SCD.