VASOOCCLUSION IN SICKLE CELL ANEMIA

描述（适用于申请人摘要）： 拟议 研究将集中在镰状细胞性贫血的血管闭塞机制上， 强调红细胞的作用， 血管因素 在 特别是， 更好地理解 需要体内机制来设计有效的疗法。 的 总的假设是，在镰状细胞性贫血中， 体内导致多效性效应如红细胞异质性， 内皮损伤、红细胞-内皮相互作用和改变 血管反应 这些异常将导致 血管闭塞危象和多器官损害。 申请人将 使用表达人α，β S，β S- 小鼠纯合β-主要缺失上的安的列斯球蛋白 背景该模型满足测试所需的基本要求 上述假设，例如红细胞异质性的存在， 血管内镰状，红细胞粘附和慢性，多发性 器官损伤 在镰状转基因小鼠中的体内研究将 通过在离体中使用人SS细胞的选定实验来补充 系统. 在转基因小鼠中，他们将测试以下假设： 上述病理表现是直接后果 血管内镰状化 拟定的体内研究将阐明： （一） 微血管异常的微流变学相关性; ii） 细胞激酶和NO的作用; iii）和改变的机制 微血管反应 用人类SS进行的拟议实验 细胞是由我们的新发现驱动的， 3蛋白在使用离体中盲肠脉管系统以及 人内皮细胞在流动室中。 的结果予以 预计研究将阐明新的机制， 人类镰状细胞病，特别是在验证 用于某些治疗方法。

DESCRIPTION (Adapted for the Applicant's Abstract): The proposed research will focus on vaso-occlusive mechanisms in sickle cell anemia, emphasizing the role of erthrocytic and vascular factors. In particular, a better understanding of the integrated physiology in vivo mechanisms is required to devise effective therapies. The overall hypothesis is that in sickle cell anemia, reversible sickling in vivo results in pleiotropic effects such as red cell heterogeneity, endothelial injury, red cell-endothelial interactions, and altered vascular responses. These abnormalities will then contribute to vasoocclusive crisis and multiple organ damage. The Applicant will use a transgenic mouse model expressing human, alpha, betaS, betaS- Antilles globins on the mouse homozygous Beta-major deletional background. This model meets the basic requirements necessary to test the above hypothesis, such as the presence of red cell heterogeneity, intravascular sickling, red cell adhesion and chronic, multiple organ damage. In vivo studies in the sickle transgenic mouse will be complemented by selected experiments with human SS cells in ex vivo systems. In the transgenic mouse, they will test the hypothesis that the above pathological manifestations are a direct consequence of intravascular sickling. The proposed in vivo studies will elucidate: i) microrheologic correlates of microvascular abnormalities; ii) the role of cytokinase and NO; iii) and mechanisms of altered microvascular responses. The proposed experiments with human SS cells are driven by our novel findings that show involvement of band 3 protein in adhesion using ex vivo mesocecum vasculature as well as human endothelial cells in a flow chamber. The results of these studies are expected to elucidate new mechanisms with relevance to the human sickle cell disease, particularly in validating the basis for certain therapeutic approaches.