VASOOCCLUSION IN SICKLE CELL ANEMIA

说明(适用于申请人的摘要)：建议 研究将集中在镰状细胞性贫血的血管闭塞机制上， 强调红细胞和血管因子的作用。在……里面 尤其是对综合生理学有了更好的理解 需要活体机制来设计有效的治疗方法。这个 总体假设是，在镰状细胞性贫血中，可逆性镰状 在体内导致多效性效应，如红细胞异质性， 内皮损伤、红细胞与内皮的相互作用和改变 血管反应。这些反常现象将导致 血管闭塞危象和多器官损害。申请者将会 使用转基因小鼠模型表达人类、阿尔法、贝塔、贝塔- 安的列斯珠蛋白对小鼠纯合子β-主要缺失的影响 背景资料。该模型满足测试所需的基本要求 上述假设，如红血球异质性的存在， 血管内镰状、红细胞黏附与慢性、多发性 器官受损。在体内对镰刀转基因小鼠的研究将 与之相辅相成的是对人SS细胞进行的体外实验 系统。在转基因小鼠中，他们将测试这样的假设： 上述病理表现是由 血管内镰刀状。拟议的活体研究将阐明： I)微血管异常的微观流变学相关性；ii) 细胞激酶和NO的作用及改变的机制 微血管反应。建议对人类SS进行的实验 细胞是由我们的新发现驱动的，这些发现表明Band参与了 体外盲肠系膜血管黏附中的蛋白以及 流室中的人体内皮细胞。这些研究的结果 预计研究将阐明新的机制，与 人类镰状细胞病，特别是在验证基础上 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.