Genetic modifiers of Sickle Cell Kidney Disease

项目摘要/摘要 这项建议提出了一个五年的研究职业发展计划，重点是前瞻性地研究角色 镰状细胞病中基因多态在慢性肾脏疾病发生发展中的作用 (SCD)。这位候选人是加州大学儿科学助理教授和肾脏科主治医师 位于孟菲斯的田纳西健康科学中心已经制定了一项研究发展计划，将提供 导师、培训和研究经验加速她成为一名独立的临床科学家 在遗传流行病学领域。为了实现候选人成为基因组专家的长期目标 对镰状细胞疾病患者慢性肾脏疾病的发展和进展的贡献， 应聘者和她的指导团队设计了以下发展计划：1)密集的、个人的 来自经验丰富的团队的指导；2)重点培训流行病学和基因组分析技术 方法；以及3)使用大量和广泛表型的患者队列的创新研究计划 基因组数据用于研究肾脏疾病的表现。候选人的研究发展计划概述了 获得在外地产生持久影响所需的知识、技能和经验的重点途径 镰状细胞病相关的肾脏疾病。 与白人相比，非裔美国人患慢性肾脏疾病的风险增加，导致 不可逆转的终末期肾病和增加的死亡率。肾脏疾病的这种种族差异提高了 遗传因素的可能性和驱动研究表明载脂蛋白L1基因之间的关联 (APOL1)和CKD的发展。虽然载脂蛋白1是肾脏发育的重要危险因素 在SCD中，这并不能完全解释增加的风险。这项提案将进一步解决 APOL1以及其他已知的与SCD中CKD相关的遗传变异。候选人将测试两个相关的 假设：A)-A3.7、Hmox1、BCL11A和APOL1等位基因独立地作用于改变起始和 肾脏疾病在SCD中的进展情况，如果将两者结合在一起考虑，将会提高预测能力 遗传风险概况(GRP)和纵向分析；以及b)在 普通非裔美国人也影响SCD肾脏疾病的发展。这 该提案将生成一个多基因遗传风险概况，以确定有更高发展风险的患者 和肾脏疾病的进展，并将为未来研究新疾病的临床研究奠定基础- 修改治疗方法。

Project Summary/Abstract This proposal presents a five-year research career development plan focused on prospectively studying the role of genetic polymorphisms in the development and progression of chronic kidney disease in sickle cell disease (SCD). The candidate, an assistant professor of pediatrics and attending nephrologist at the University of Tennessee Health Science Center at Memphis, has devised a research development plan that will provide mentorship, training and research experience to expedite her development into an independent clinician scientist in the field of genetic epidemiology. To achieve the candidate’s long-term goal of becoming an expert in genomic contributions to the development and progression of chronic kidney disease in individuals with sickle cell disease, the candidate and her mentorship team have devised the following development plan: 1) intensive, personal mentorship from an experienced team; 2) focused training on techniques in epidemiology and genomic analysis methods; and 3) an innovative research plan using a large and extensively phenotyped patient cohort with genomic data to study kidney disease manifestations. The candidate’s research development plan outlines a focused route to obtain the knowledge, skills and experience necessary to make a lasting impact in the field sickle cell disease-associated kidney disease. Compared with whites, African Americans have an increased risk for chronic kidney disease, resulting in irreversible end stage kidney disease and increased mortality. This racial disparity in kidney disease raised the possibility of genetic contributors and drove studies showing an association between the apolipoprotein L1 gene (APOL1) and development of CKD. Although APOL1 is a significant risk factor for the development of kidney disease in SCD, it does not fully account for the increased risk. This proposal will further address the role of APOL1 as well as other known genetic variants associated with CKD in SCD. The candidate will test two related hypotheses: a) -a3.7, HMOX1, BCL11A and APOL1 alleles act independently to modify the onset and progression of kidney disease in SCD and will have improved predictive power when considered together in a genetic risk profile (GRP) and analyzed longitudinally; and b) known genetic modifiers of CKD discovered in the general African American population also influence the development of kidney disease in SCD. This proposal will generate a multi-gene genetic risk profile to identify patients at increased risk for development and progression of kidney disease and will set the stage for future clinical studies investigating novel disease- modifying therapies.