Pathways of Cell-Free Hemoglobin in Sickle Cell Nephropathy

慢性肾脏疾病存在于很大比例的成人镰状细胞病(SCD)中，并且是 与发病率和早期死亡率增加有关。慢性肾脏疾病的发病机制 不幸的是，人们对镰状细胞肾病的研究知之甚少，预防和治疗镰状细胞肾病的疗法也很少。 急需之物。这项建议将利用申请人的K23和R03奖励的稳健的初步数据 创新性地解决肾脏疾病的机制途径和易感性，并研究 减轻SCD肾损害的有针对性的干预。潜在的假设是无细胞的 如果不能有效地清除和清除血红蛋白，则可介导对肾皮质和微血管的损害 已处理。申请者将通过三个具体目标应用令人兴奋的初步数据来检验这一假设。 具体目标#1将确定幽门螺杆菌的功能变异是否为无细胞血红蛋白的主要清除剂 在循环中，以及Hmox1，一种降解血红素的限速酶，与急性肾脏有关 血管闭塞危象期间，当无细胞血红蛋白浓度增加时的损伤风险 2折。具体目标#2将确定无细胞血红蛋白是否会导致肾脏微血管功能障碍 通过血栓调节蛋白的异常功能，血栓调节蛋白是一种内皮结合蛋白，对维持血管至关重要 健康。具体目标#3将调查口服镰刀小分子抑制剂Voxelotor 血红蛋白聚合和溶血，减少无细胞血红蛋白暴露和对肾脏的损害 在转基因镰刀鼠身上。 将无细胞血红蛋白加工的遗传分析与改善血管功能或治疗相结合 减少肾脏中的游离血红蛋白暴露将有助于对其机制的更深层次的理解 并指导镰状细胞肾病的个体化和预防性治疗策略。这 研究团队具有非凡的地位，能够通过强大的历史经验实现本提案中概述的目标 生产力和制度环境。伊利诺伊大学芝加哥分校综合镰刀 细胞中心照顾800多名SCD患者，并拥有成功实施 研究性研究。目前，可用于治疗SCD的治疗选择有限。 更好地了解肾脏疾病的易感性和途径可能会 对这一未得到充分服务的高危人群产生重大影响。

Chronic kidney disease is present in a large proportion of adults with sickle cell disease (SCD) and is associated with increased morbidity and early mortality. The mechanisms for how chronic kidney disease develops are, unfortunately, poorly understood and therapies to prevent and treat sickle cell nephropathy are urgently needed. This proposal will leverage robust preliminary data from the applicant's K23 and R03 awards to innovatively address the mechanistic pathways and susceptibilities for kidney disease and investigate targeted interventions to mitigate kidney damage in SCD. The underlying hypothesis is that cell-free hemoglobin mediates damage to the kidney cortex and microvasculature if not efficiently scavenged and processed. The applicant will apply exciting preliminary data to test this hypothesis via three specific aims. Specific aim #1 will determine whether functional variants in HP, the main scavenger of cell-free hemoglobin in circulation, and HMOX1, the rate limiting enzyme for degrading heme, are associated with acute kidney injury risk during a vaso-occlusive crisis, when concentrations of cell-free hemoglobin increase approximately 2-fold. Specific aim #2 will determine whether cell-free hemoglobin leads to kidney microvascular dysfunction through aberrant function of thrombomodulin, an endothelial bound protein critical for maintaining vascular health. Specific aim #3 will investigate whether voxelotor, an oral small molecular inhibitor of sickle hemoglobin polymerization and hemolysis, reduces cell-free hemoglobin exposure and damage to the kidney in transgenic sickle mice. Integrating genetic analyses of cell-free hemoglobin processing with therapies to improve vascular function or reduce cell-free hemoglobin exposure to the kidney will lead to a deeper understanding for the mechanisms of kidney damage and guide individualized and preventive therapeutic strategies for sickle cell nephropathy. This research team is exceptionally positioned to achieve the goals outlined in this proposal through a strong history of productivity and the institutional environment. The University of Illinois at Chicago Comprehensive Sickle Cell Center cares for over 800 SCD patients and has a long-standing tradition of successful implementation of research studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population.