REGULATION OF SICKLE CELL PHOSPHOLIPID ORGANIZATION

暴露红细胞的磷脂酰丝氨酸(PS)的存在与糖尿病的病理生理学有关。 镰状细胞病(SCD)，包括止血不平衡、中风风险、红细胞增加 血管内皮细胞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中存在如此高的水平，以及它们是如何导致 SCD病理学。我们假设了一个新的事件链，在这个链中(炎症)脂质 介体触发信号转导通路，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与细胞的相互作用。要解决动态 会导致PS暴露并影响红细胞内皮细胞相互作用的机制，我们有 制定了以下具体目标：1.评估SCD中炎性脂质介质的增加对亚群中磷脂不对称性丢失的影响 镰刀状的细胞。II.探讨红细胞胞内信号通路在糖尿病发病中的作用 对翻转酶和扰乱酶的调节，以及III.研究改变的作用 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。至 为了实现这些目标，我们将使用生物化学和细胞的多学科方法 在明确的条件下研究红细胞和内皮细胞的生物学技术。我们 将使用SCD患者的血液样本以及SCD的转基因小鼠模型。我们会 测量体内LPA等脂质介质的存在，测量LPA在体内的生成 并确定它的作用。我们将把体外研究的数据与SCD的体内研究结果联系起来 血管闭塞危象、中风和急性胸部综合征的患者，以及我们的小鼠 SCD的型号。总之，我们的结果可能预示着新的治疗方案 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.