GENETIC THERAPY FOR SICKLE CELL DISEASE

该项目将测试抗炎剂阻止直接测量的血液流量减少的能力。 镰状细胞病患者的皮肤、深部组织和骨髓。我们假设治疗性干预 中断镰状红细胞、白细胞、血小板与血管内皮细胞之间的黏附相互作用 消除血管闭塞、降低血红蛋白饱和度和释放血管损伤的措施 间歇性缺氧。而镰状细胞病(SCD)被认为是明显的红细胞镰状、与镰状细胞相关的急性发作。 即使在非危象期，血管闭塞也会持续发生。这些急性和慢性疾病的累积效应 慢性过程是终末器官损伤。最近来自动物模型的数据强调了白细胞的关键重要性 黏附于血管内皮细胞。因此，干扰粘合剂形成的治疗方法很可能 白细胞、镰刀状红细胞和血管内皮细胞之间的相互作用将减少血管和终末器官的损伤。 低氧会引发红血球凝集。对SCD儿童的睡眠研究表明，10到40次饱和度降低 每晚发生，血氧饱和度降至75%至85%。我们直接测量了血流量的减少 镰状细胞病受试者对氮气诱导的低氧反应。这些降幅是 正常对照组(P&lt；.001)。我们将在人类中开发这种血管闭塞模型，并将研究扩展到包括 低氧致血管损伤标志物炎症介质(sLCAM、sVCAM)变化的检测 (循环内皮细胞(EC)和EC激活)和深部组织血流量的测量(超声和BOLD 核磁共振)。这些参数将在氮气诱导的缺氧和自然缺氧的情况下进行测量。 在睡眠中发生的。然后我们会用消炎药来阻断血流的变化，增加 在这些具有良好特征的模型中检测到血管损伤的标记。如果这些代理商成功，我们有直接的 在人类中有证据表明炎症在血管闭塞中起作用。此外，该模型还可以用于文本 镰状细胞病的候选治疗方法。 虽然不在本提议的范围内，但我们预计，消除低氧的治疗干预措施 血流减少；在这些人中检测到的缺氧反应和血管损伤标志物的变化 如果在更大的临床试验中进行测试，模型将减少危象发生的频率，并减轻终末器官损害的程度。

This project will test theability of anti-inflammatory agents to block decrease in blood flow directly measured in the skin, deep tissue and bone marrow of subjects with sickle cell disease. We hypothesize that therapeutic interventions that interrupt adhesive interactions between sickle erythrocytes, leukocytes, platelets and vascular endothelium will lessen or abrogate the vaso occlusion, hemoglobin desaturations, and release of measures of vascular damage induced by intermittent hypoxia. While sickle cell disease (SCD) is thought of as acute episodes of marked RBC sickling, sicklerelated vaso occlusion occurs continually even during non-crisis periods. The cumulative effect of these acute and chronic processes is end-organ damage. Recent data from animal models underscore the critical importance of leukocyte adhesion to the vascular endothelium. It is therefore likely that therapies that interfere with the formation of the adhesive interactions between leukocytes, sickle red cells and vascular endothelium will decrease vascular and end-organ damage. RBC siekling is triggered by hypoxia. Sleep studies in SCD children demonstrate that 10 to 40 episodes of desaturation occur each night with oxygen saturation dropping to 75 to 85%. We directly measured decreases in blood flow in response to nitrogen-induced hypoxia in subjects with sickle cell disease. These decreases are six-times greater than normal controls (p<.001). We will develop this model ofvaso occlusion in humans and extend the studies to include measurement of hypoxia-induced changes in inflammatory mediators (slCAM, sVCAM), markers of vascular damage (circulating endothelial cells (EC) and EC activation), and measures of deep tissue blood flow (ultrasound and BOLD MRI). These parameters will be measured in response to nitrogen-induced hypoxia as well as hypoxic episodes naturally occurring during sleep. We will then use anti-inflammat0ry agents to block the changes in blood flow and increase in markers of vascular damage detected in these well-characterized models. If these agents are successful, we have direct evidence in humans that inflammation plays a role in vas0 occlusion. Furthermore, this model may serve to text candidate treatments for sickle cell disease. While not within the scope of the present proposal, we anticipate that therapeutic interventions that abrogate hypoxiainduced blood flow decreases; hypoxie responses and changes in markers of vascular damage detected in these human models will decrease frequency of crisis and lessen the degree of end-organ damage if tested in larger clinical trials.