Pathways of Cell-Free Hemoglobin in Sickle Cell Nephropathy

镰状细胞肾病中无细胞血红蛋白的通路

基本信息

批准号：
10443592
负责人：
Santosh Saraf
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443592
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Adult Affect African American population Animal Model Award Binding Proteins Biological Markers Blood Circulation Blood Vessels Caring Catabolism Cells Cessation of life Chicago Chronic Kidney Failure Complement Activation Creatinine Data Disease Disease Progression Endothelial Cells Endothelium Environment Enzymes Exposure to Functional disorder Future Gene Expression Profile Goals Haptoglobins Health Heme Hemoglobin Hemoglobinuria Hemolysis Hemolytic-Uremic Syndrome Histologic Illinois Impairment Injury to Kidney Intervention Kidney Kidney Diseases Mediating Metabolism Microvascular Dysfunction Morbidity - disease rate Mus Oral Organ Oxidative Stress Pathway interactions Patients Persons Phenotype Plasma Plasma Cells Play Positioning Attribute Pre-Eclampsia Predisposition Preventive Process Productivity Protein C Recording of previous events Renal function Research Risk Role Sepsis Serum Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Tandem Repeat Sequences Testing Therapeutic Thrombomodulin Time Toxic effect Transgenic Organisms Translational Research Universities Urine Variant Vascular Diseases contrast enhanced disorder risk endothelial dysfunction genetic analysis heme oxygenase-1 high risk high risk population improved innovation insight kidney cell kidney cortex mortality novel oxidative damage polymerization prevent rat KIM-1 protein renal damage research study sickling small molecular inhibitor therapy development ultrasound vaso-occlusive crisis

项目摘要

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.

慢性肾脏疾病存在很大一部分患有镰状细胞病（SCD）的成年人与发病率和早期死亡率的增加有关。慢性肾脏疾病的机制不幸的是，发育的理解很差，可以预防和治疗镰状细胞肾病的疗法是迫切需要。该建议将利用申请人的K23和R03奖的强大初步数据创新解决肾脏疾病的机械途径和敏感性有针对性的干预措施减轻SCD中的肾脏损伤。潜在的假设是无细胞血红蛋白介导对肾脏皮层和微脉管系统的损害，如果没有有效清除并且处理。申请人将通过三个特定目标应用令人兴奋的初步数据来检验该假设。特定目标＃1将确定HP中的功能变体是否是无细胞血红蛋白的主要清除剂在循环和HMOX1中，降解血红素的速率限制酶与急性肾脏有关当无细胞血红蛋白的浓度大约增加时，在血管结合性危机期间的损伤风险大约 2倍。具体目标＃2将确定无细胞的血红蛋白是否导致肾脏微血管功能障碍通过血小板蛋白的异常功能，血栓形成蛋白是一种维持血管至关重要的内皮结合蛋白健康。特定的目标＃3将调查镰刀的口服小分子抑制剂的素体血红蛋白聚合和溶血，减少无细胞的血红蛋白暴露和肾脏损害在转基因镰刀小鼠中。将无细胞血红蛋白加工的遗传分析与改善血管功能或减少无细胞的血红蛋白暴露于肾脏将导致对机制的更深入了解肾脏损伤并指导镰状细胞肾病的个性化和预防性治疗策略。这研究团队非常适合通过悠久的历史实现该提案中概述的目标生产力和机构环境。伊利诺伊大学芝加哥综合镰刀细胞中心关心800多名SCD患者，并具有成功实施的长期传统研究。目前，只有有限的治疗方法可以治疗SCD。对肾脏疾病的敏感性和途径有更好的了解可能有可能有对这个服务不足的高风险人群的重大影响。