Genetic modifiers of Sickle Cell Kidney Disease

镰状细胞性肾病的基因修饰

• 批准号: 10370914
• 负责人: Rima Zahr
• 金额: $ 17.68万
• 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/10370914
• 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; Onset of illness; Organ; Outcome; Oxidative Stress; Participant; Pathology; Patients; Pediatrics; Phenotype; 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; Variant; beta Globin; biobank; career development; clinical care; cohort; design; efficacy evaluation; experience; genetic epidemiology; genetic variant; genome wide association study; genomic data; high risk; 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.

项目总结/摘要 该提案提出了一项为期五年的研究职业发展计划，重点是前瞻性地研究 遗传多态性在镰状细胞病慢性肾脏疾病的发生和发展中的作用 （SCD）。这位候选人，一位儿科助理教授，也是芝加哥大学的肾病学家。 位于孟菲斯的田纳西健康科学中心制定了一项研究开发计划，该计划将提供 导师，培训和研究经验，以加快她发展成为一个独立的临床科学家 在遗传流行病学领域。为了实现候选人成为基因组学专家的长期目标， 在镰状细胞病患者中促进慢性肾病的发展和进展， 候选人和她的导师团队制定了以下发展计划：1）密集，个人 由经验丰富的团队提供指导; 2）重点培训流行病学和基因组分析技术 方法;和3）一个创新的研究计划，使用一个大的和广泛的表型患者队列， 基因组数据来研究肾脏疾病的表现。候选人的研究发展计划概述了一个 获得在实地产生持久影响所需的知识、技能和经验的重点路线 镰状细胞病相关肾病。 与白人相比，非裔美国人患慢性肾脏疾病的风险增加， 不可逆的终末期肾病和死亡率增加。这种肾脏疾病的种族差异提高了 遗传贡献者的可能性，并推动研究表明载脂蛋白L1基因之间的关联 （APOL 1）和慢性肾脏病的发展。虽然APOL 1是肾脏发育的重要危险因素， 但这并不能完全解释SCD的风险增加。这项建议将进一步处理以下方面的作用： APOL 1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、HMOX 1、BCL 11 A和APOL 1等位基因独立地起作用以改变发病和 SCD中肾脏疾病的进展，并且当在一个 遗传风险概况（GRP）并进行纵向分析;和B）在以下人群中发现的CKD的已知遗传修饰物： 一般的非裔美国人群体也影响SCD中肾脏疾病的发展。这 一项提案将产生一个多基因遗传风险概况，以确定患者的发展风险增加 以及肾脏疾病的进展，并将为未来研究新型疾病的临床研究奠定基础- 改良疗法