Pathways of Cell-Free Hemoglobin in Sickle Cell Nephropathy

慢性肾脏疾病存在于大部分患有镰状细胞病（SCD）的成年人中， 与发病率和早期死亡率的增加有关。慢性肾脏疾病的发病机制 不幸的是，对镰状细胞肾病的发展知之甚少，预防和治疗镰状细胞肾病的疗法 迫切需要。该提案将利用申请人K23和R03奖项的可靠初步数据 创新性地解决肾脏疾病的机制途径和易感性，并研究 有针对性的干预措施，以减轻SCD的肾损伤。潜在的假设是， 血红蛋白如果不能被有效清除， 已处理。申请人将通过三个具体目标应用令人兴奋的初步数据来验证这一假设。 具体目标#1将确定HP（无细胞血红蛋白的主要清除剂）中是否存在功能变体 在循环中，和HMOX1，降解血红素的限速酶，与急性肾功能衰竭有关。 当无细胞血红蛋白浓度大约增加时， 2倍。具体目标#2将确定无细胞血红蛋白是否会导致肾微血管功能障碍 通过血栓调节蛋白（一种对维持血管至关重要的内皮结合蛋白）的异常功能 健康具体目标#3将研究是否voxelotor，一种口服小分子镰刀抑制剂， 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 在转基因镰刀小鼠中。 将无细胞血红蛋白处理的遗传分析与改善血管功能的治疗相结合， 减少无细胞血红蛋白暴露于肾脏将导致对 并指导镰状细胞性肾病个体化和预防性治疗策略。这 研究团队非常有能力通过强大的历史来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 细胞中心照顾800多名SCD患者，并具有成功实施 调查研究。目前，仅有有限的治疗选择可用于治疗SCD。 更好地了解肾脏疾病的易感性和途径可能会 这对这些服务不足的高危人群产生了重大影响。

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.