Genetic modifiers of Sickle Cell Kidney Disease

镰状细胞性肾病的基因修饰

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要该提案提出了一个五年研究职业发展计划，重点是前瞻性研究该角色遗传多态性在镰状细胞病慢性肾病发生和进展中的作用 (SCD) 候选人，英国大学儿科助理教授兼主治肾病专家。位于孟菲斯的田纳西州健康科学中心制定了一项研究开发计划，该计划将提供指导、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实现候选人成为基因组专家的长期目标。对镰状细胞病患者慢性肾病的发生和进展的贡献，候选人和她的导师团队制定了以下发展计划：1）强化的、个人的 2）流行病学和基因组分析技术的重点培训方法；3) 使用大量且广泛表达的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概述了候选人的研究发展计划。获得在该领域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病的风险更高，导致不可逆转的终末期肾病和死亡率的增加提高了肾病的种族差异。遗传因素的可能性，并推动研究表明载脂蛋白 L1 基因之间存在关联 (APOL1) 和 CKD 的发展尽管 APOL1 是肾脏发育的重要危险因素。疾病在 SCD 中的作用，它并没有完全解释增加的风险。 APOL1 以及与 SCD 中 CKD 相关的其他已知基因变异。候选人将测试两种相关的基因变异。假设：a) -a3.7、HMOX1、BCL11A 和 APOL1 等位基因独立作用以改变起始和 SCD 中肾脏疾病的进展，并且在综合考虑时将具有更高的预测能力遗传风险概况 (GRP) 并进行纵向分析；b) 发现的已知 CKD 遗传修饰因子一般非裔美国人群体也影响 SCD 肾脏疾病的发展。该提案将生成多基因遗传风险概况，以识别发育风险增加的患者和肾脏疾病的进展，并将为未来调查新疾病的临床研究奠定基础- 修改疗法。