Genetics and Genomics of Sickle Cell Nephropathy.

镰状细胞肾病的遗传学和基因组学。

• 批准号: 9129710
• 负责人: Santosh Saraf
• 金额: $ 18.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129710
• 关键词: Address; Adult; Affect; African; African American; Award; Bioinformatics; Blood capillaries; Candidate Disease Gene; Caring; Cells; Cessation of life; Chicago; Chronic Kidney Failure; Clinical Research; Clinical Sciences; Creatinine; Cross-Sectional Studies; DNA; Data; Development; Disease; Early Intervention; Enrollment; Environment; Exposure to; Future; Gene Chips; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic approach; Genomics; Genotype; Globin; Goals; HK2 gene; Health; Hemodialysis; Hemoglobin; Hemoglobinuria; Hemolysis; Human; Hypertension; Illinois; Immune response; Inflammatory Response; Injury; Intervention; Kidney; Kidney Diseases; Kidney Transplantation; MAPK8 gene; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Modeling of Functional Interactions; Morbidity - disease rate; Pathway Analysis; Pathway interactions; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Physicians; Plasma; Population; Positioning Attribute; Predisposition; Process; Productivity; Professional Competence; Program Development; Public Health Schools; Publishing; Pulmonary Hypertension; Quantitative Trait Loci; RNA; Recombinant Proteins; Recording of previous events; Registries; Reperfusion Injury; Research; Research Personnel; Risk Factors; SNP array; Scientist; Serum; Sickle Cell; Sickle Cell Anemia; Testing; Therapeutic; Time; Transfection; Translational Research; Tubular formation; Universities; Up-Regulation; Urine; Variant; Walking; base; capillary; career development; cohort; differential expression; follow-up; genetic approach; genetic variant; genome-wide; haptoglobin-related protein; high risk; improved; kidney cell; mortality; novel; oxidative damage; prevent; programs; prospective; protein complex; research study; sickling; targeted sequencing; training opportunity; trait; urinary

 DESCRIPTION (provided by applicant): The applicant for this K23 Mentored Patient-Oriented Research Career Development Award is a physician scientist with a focus on developing improved care for patients with sickle cell disease (SCD). Chronic kidney disease is present in a large proportion of adults with SCD and is associated with morbidity and early mortality. However, the pathways for sickle nephropathy are unfortunately poorly understood. This proposal will leverage robust genomic strategies to innovatively address mechanistic pathways and susceptibilities for chronic kidney disease in patients with SCD. The underlying hypothesis is that genetic variation existing outside the ß-globin gene-like cluster is centrally involved in influencing the propensity to develop chronic kidney disease. The applicant will apply exciting preliminary data to develop a candidate gene approach and mechanistic pathways to test this hypothesis via three specific aims. Specific aim #1 will utilize a genomic approach to identify polymorphisms and expression quantitative trait loci (eQTL) in candidate genes to highlight functional pathways for chronic kidney disease in SCD. Specific aim #2 will determine whether the identified gene variants are associated with the progression of chronic kidney disease in a longitudinal cohort to help recognize high-risk SCD patients for kidney disease and guide earlier intervention strategies. Specific aim #3 will investigate mechanisms for understanding how variants in APOL1 and HMOX1 contribute to sickle cell nephropathy. With the guidance of a strong team of mentors, this proposal includes a comprehensive development program incorporating training opportunities through the University of Illinois at Chicago (UIC) School of Public Health, UIC Center for Clinical and Translational Sciences Program, and Department of Medicine. The goals of this proposal are to enhance the applicant's career development and skills in bioinformatic, biostatistical, and translational methods in order to conduct research for understanding the pathobiology of kidney disease in patients with SCD. The applicant is exceptionally positioned to achieving the goals outlined in this proposal through a strong history of productivity and the institutional environment which includes the UIC Comprehensive Sickle Cell Center which cares for over 800 SCD patients and has a long-standing tradition of successful implementation of clinical 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 and will facilitate the long-term goals of the applicant in becoming a successful and independent translational researcher focusing on sickle cell nephropathy.

 描述（由适用提供）：该K23指导的以患者为导向的研究职业发展奖的申请人是一名物理科学家，专注于为镰状细胞疾病（SCD）的患者开发改进的护理。慢性肾脏疾病有很大一部分患有SCD的成年人，并且与发病率和早期死亡率有关。但是，不幸的是，镰状肾病的途径是不幸的。该建议将利用强大的基因组策略来创新地解决SCD患者慢性肾脏疾病的机械途径和敏感性。潜在的假设是，β-珠蛋白基因样簇以外存在的遗传变异集中参与 影响发展慢性肾脏疾病的诺言。申请人将采用令人兴奋的初步数据来开发候选基因方法和机械途径，以通过三个特定目标来检验该假设。特定目标＃1将利用一种基因组方法来鉴定候选基因中的多态性和表达定量性状位置（EQTL），以突出SCD中慢性肾脏病的功能途径。具体目标＃2将确定确定的基因变异是否与纵向队列中慢性肾脏疾病的进展有关，以帮助识别高风险的SCD患者患有肾脏疾病并指导早期的干预策略。特定目标＃3将研究理解Apol1和Hmox1中变异的机制。在强大的导师团队的指导下，该建议包括一项全面的开发计划，该计划通过芝加哥大学（UIC）公共卫生学院，UIC临床和翻译科学计划中心和医学系进行了培训机会。该建议的目标是增强申请人的职业发展和生物信息，生物统计和转化方法的技能，以进行研究 了解SCD患者肾脏疾病的病理生物学。适用的定位是通过强大的生产力和机构环境包括UIC综合镰状细胞中心，它在此提案中实现了本提案中概述的目标，该中心关心800多名SCD患者，并具有成功实施临床研究的长期传统。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会对这种服务不足的高风险人群产生重大影响，并将促进该应用程序的长期目标，成为一名致力于镰状细胞肾病的成功和独立翻译的研究人员。