Cytokines in Sickle Cell Volume Regulation

镰状细胞体积调节中的细胞因子

• 批准号: 6952021
• 负责人: ALICIA RIVERA
• 金额: $ 16.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952021
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; blood volume; chloride channels; cytokine; endothelin; enzyme activity; erythrocytes; hormone receptor; hypoxia; inhibitor /antagonist; laboratory mouse; magnesium; potassium channel; protein kinase C; sickle cell anemia; sodium

DESCRIPTION (provided by applicant): The objective of this application is to provide the minority applicant with an additional experience that will result in her becoming an independent and RO1 funded investigator. The long-range goal of the investigator is to establish the pathophysiological mechanism(s) that link sickling formation and endothelium activation in sickle cell disease. The central hypothesis of this application is that the elevated systemic and local concentrations of cytokines are major contributors to the pathogenesis of irreversible sickle cell formation via alterations of erythrocyte volume regulatory pathways. We will test the hypothesis by characterizing the mechanism(s) by which ET-1 induces dehydration in sickle erythrocytes and the contribution of inducible signaling factors to this effect in sickle cell disease. We plan to test our central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: 1) Identify the mechanism(s) by which ET-1 receptors regulate sickle erythrocyte cellular volume. We will test the hypothesis that ET-1 receptor induces red cell dehydration via protein kinase C activation. 2) Identify the mechanism(s) by which ET-1 receptors regulate cellular Mg in sickle erythrocytes. We hypothesize that the relationship between the Na/Mg exchange and ET-1 receptor is disrupted in sickle erythrocytes leading to activation of the K/CI cotransport which leads to further red cell dehydration in vivo. 3) Identify the effects of ET-1 receptor antagonist treatment on hypoxic induced sickle cell formation in vivo. We hypothesize that these antagonists may blunt ET-1-mediated effects in hypoxic mice. We also hypothesize that this inhibition might be mediated by a reduction in endothelium activation. The research proposed in this application is significant because it will provide novel information for the use of ET-1 receptor antagonists to reduce irreversible sickle cells and a more comprehensive knowledge of erythrocyte volume regulatory mechanism(s) that will help to develop novel strategies to reduce sickle cell formation, and decrease the occurrence of vaso-occlusive episodes.

描述（由申请人提供）： 本申请的目的是为少数族裔申请人提供额外的经验，这将导致她成为独立且RO1资助的研究者。研究者的远距离目标是建立将镰状形成和镰状细胞病中内皮激活联系起来的病理生理机制。该应用的中心假设是，细胞因子的全身浓度和局部浓度升高是通过改变红细胞体积调节途径的改变不可逆的镰状细胞形成的发病机理。我们将通过表征ET-1诱导镰状红细胞脱水的机制来检验假设，以及可诱导信号因子对镰状细胞疾病中这种作用的贡献。我们计划通过追求以下特定目的来检验我们的中心假设，并实现本应用的总体目标：1）确定ET-1受体调节镰状红细胞细胞体积的机制。我们将检验以下假设：ET-1受体通过蛋白激酶C激活诱导红细胞脱水。 2）确定ET-1受体在镰状红细胞中调节细胞MG的机制。我们假设Na/Mg交换与ET-1受体之间的关系在镰状红细胞中被破坏，从而导致K/CI共转移激活，从而导致体内进一步的红细胞脱水。 3）确定ET-1受体拮抗剂治疗对体内缺氧诱导的镰状细胞形成的影响。我们假设这些拮抗剂可能在低氧小鼠中钝化ET-1介导的作用。我们还假设，这种抑制可能是由内皮激活减少来介导的。该应用中提出的研究非常重要，因为它将提供新的信息，以使用ET-1受体拮抗剂减少不可逆的镰状细胞，并更全面地了解红细胞体积调节机制，这将有助于制定新的策略，以减少镰状细胞形成，并减少血管 - 核判断性剧集的发生。