Genetic modifiers of Sickle Cell Kidney Disease

镰状细胞性肾病的基因修饰

• 批准号: 10557196
• 负责人: Rima Zahr
• 金额: $ 16.86万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557196
• 关键词: Address; Adult; Affect; African American population; Age; Albumins; Albuminuria; Alleles; Apolipoproteins; BMP4; Blood Vessels; Candidate Disease Gene; Caring; Chicago; Child; Childhood; Chronic Kidney Failure; Clinic; Clinical; Clinical Markers; Clinical Research; Complex; Creatinine; Cross-Sectional Studies; Data; Development; Development Plans; Disease; End stage renal failure; Enrollment; Epidemiology; Functional disorder; Future; GSTM1 gene; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic study; Genomics; Glomerular Filtration Rate; Goals; Health Sciences; Hematological Disease; Hemolysis; Hypertension; Hypoxia; Illinois; Individual; Inflammation; Injury to Kidney; Kidney Diseases; Kidney Failure; Knowledge; Longevity; Longitudinal cohort; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Morbidity - disease rate; NMT2 gene; Organ; Outcome; Oxidative Stress; Participant; Pathology; Patients; Pediatrics; Phenotype; Polymers; Prospective Studies; Renal function; Renin-Angiotensin-Aldosterone System; Reporting; Research; Risk; Risk Factors; Role; Route; Saint Jude Children' s Research Hospital; Scientist; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Structural defect; Techniques; Tennessee; Testing; Thalassemia; Training; UMOD gene; Universities; Urine; VEGFA gene; Variant; alpha-Thalassemia; beta Globin; biobank; career development; clinical care; cohort; design; efficacy evaluation; experience; genetic epidemiology; genetic selection; genetic variant; genome wide association study; genomic data; high risk; high risk population; improved; innovation; intervention program; longitudinal analysis; mortality; mortality risk; nephrogenesis; novel; polymerization; prevent; professor; prospective; racial disparity; renal damage; research and development; risk variant; skills

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.

项目摘要/摘要 该建议提出了一项五年的研究职业发展计划，重点是前瞻性地研究角色 镰状细胞疾病中慢性肾脏疾病发育和进展中遗传多态性的 （SCD）。候选人，儿科助理教授和大学的肾脏科医生 孟菲斯的田纳西州健康科学中心已经制定了一项研究开发计划，将提供 跨越，培训和研究经验，将她的发展加快成为独立的临床科学家 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 镰状细胞疾病个体慢性肾脏疾病发展和进展的贡献， 候选人和她的心态团队已经制定了以下发展计划：1）密集，个人 经验丰富的团队的指导； 2）专注于流行病学和基因组分析技术的培训 方法; 3）使用大型且广泛的表型患者队列的创新研究计划 研究肾脏疾病表现的基因组数据。候选人的研究发展计划概述了 专注的途径，以获取在现场产生持久影响所必需的知识，技能和经验 镰状细胞疾病相关的肾脏疾病。 与白人相比，非裔美国人患慢性肾脏疾病的风险增加，导致 不可逆转的末期肾脏疾病和死亡率增加。肾脏疾病的这种种族差异增加了 遗传贡献者和驱动研究的可能性显示了载脂蛋白L1基因之间的关联 （APOL1）和CKD的发展。虽然APOL1是肾脏发展的重要危险因素 SCD中的疾病并不能完全解释风险的增加。该建议将进一步解决 APOL1以及与SCD中CKD相关的其他已知遗传变异。候选人将测试两个相关的 假设：A）-A3.7，HMOX1，BCL11A和APOL1等位基因独立起作用以修改发作和 在SCD中肾脏疾病的进展，当在A中一起考虑时，预测能力将提高 遗传风险概况（GRP）并纵向分析； b）在中发现的CKD的已知遗传修饰符 非裔美国人的总人口也影响SCD中肾脏疾病的发展。这 提案将产生多基因遗传风险概况，以识别患者的发展风险增加 和肾脏疾病的进展，并将为研究新疾病的未来临床研究奠定阶段 - 修改疗法。