Genetics and Genomics of Sickle Cell Nephropathy.

 描述(由申请人提供)：这项K23指导的以患者为导向的研究职业发展奖的申请者是一名内科科学家，专注于为镰状细胞病(SCD)患者开发更好的护理。慢性肾脏疾病存在于很大比例的SCD成人患者中，并且与发病率和早期死亡率有关。然而，不幸的是，镰状肾病的发病途径知之甚少。这项建议将利用强大的基因组战略，创新地解决SCD患者慢性肾脏疾病的机制途径和易感性。潜在的假说是，存在于贝珠蛋白类基因簇之外的遗传变异集中参与了 影响患慢性肾脏疾病的倾向。申请者将应用令人兴奋的初步数据来开发候选基因方法和机制路径，以通过三个特定的目标来检验这一假设。具体目标#1将利用基因组方法识别候选基因中的多态和表达数量性状基因座(EQTL)，以突出SCD慢性肾脏疾病的功能途径。具体目标#2将在纵向队列中确定已识别的基因变异是否与慢性肾脏疾病的进展相关，以帮助识别肾脏疾病的高危SCD患者并指导早期干预策略。具体目标#3将调查了解APOL1和Hmox1变异如何导致镰状细胞性肾病的机制。在强大的导师团队的指导下，这项建议包括一个全面的发展计划，其中包括通过伊利诺伊大学芝加哥分校(UIC)公共卫生学院、UIC临床与转化科学中心计划和医学系提供的培训机会。这项建议的目标是提高申请人的职业发展和在生物信息学、生物统计学和翻译方法方面的技能，以便开展以下研究 了解系统性红斑狼疮患者肾脏疾病的病理生物学。申请者通过强大的生产力历史和制度环境(包括UIC综合镰刀细胞中心)处于特殊地位，能够实现本提案中概述的目标。UIC综合镰刀细胞中心照顾800多名SCD患者，具有成功实施临床研究的长期传统。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些服务不足的高危人群产生重大影响，并将有助于申请者成为一名成功的、专注于镰状细胞肾病的独立翻译研究人员的长期目标。

 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.