Biomarkers of Immune Activation in African Americans with CKD

患有 CKD 的非裔美国人免疫激活的生物标志物

• 批准号: 10702184
• 负责人: Teresa Chen
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10702184
• 关键词: APOL1 gene; Adaptive Immune System; Affect; African American; African American population; African ancestry; American; Amlodipine; Applications Grants; Atherosclerosis Risk in Communities; Award; Biological Markers; Biology; Blood Pressure; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Complex; Data; Data Analyses; Development; Dietary Factors; Dietary Potassium; Dietary Sodium; Disease Progression; Doctor of Philosophy; End stage renal failure; Endothelial Cells; Ensure; Environment; Epidemiology; European; Experimental Models; Funding Mechanisms; Future; General Population; Genotype; Goals; High Prevalence; Hour; Human body; Hypertension; Immune; Immunologic Markers; In Vitro; Individual; Innate Immune System; Intake; Interferon Gamma Receptor Beta Chain; Interferon Type II; Intervention; Invaded; Investigation; K-Series Research Career Programs; Kidney Diseases; Letters; Link; Measurement; Measures; Mentors; Mentorship; Methods; Metoprolol; Molecular Epidemiology; Nephrology; Outcome; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phase; Populations at Risk; Potassium; Proteinuria; Ramipril; Randomized; Renal function; Reproducibility; Research; Research Design; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Serum; Sodium; Sodium Chloride; System; TNF gene; Time; Training; Tryptophan Metabolism Pathway; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Universities; Urine; Visit; Water; blood pressure control; blood pressure intervention; blood pressure medication; career; cohort; demographics; diabetic patient; endothelial dysfunction; experience; fatty acid oxidation; follow-up; genetic epidemiology; genetic risk factor; high risk; high risk population; immune activation; improved; insight; medical schools; metabolomics; microorganism; non-diabetic; novel; podocyte; predictive marker; professor; randomized trial; receptor; risk variant; skills; treatment arm; trial design

PROJECT SUMMARY/ABSTRACT Teresa K. Chen, MD, MHS is an Assistant Professor in the Division of Nephrology at Johns Hopkins University School of Medicine. She is applying for a K08 Mentored Clinical Scientist Research Career Development Award in order to acquire the necessary skills and mentored research experience to become an independent investigator in the field of chronic kidney disease (CKD). The proposed 5-year plan includes advanced coursework in epidemiology; practical experience in the measurement of biomarkers; and mentorship by an extraordinarily experienced, committed and diverse mentorship team [co-primary mentors, Lawrence Appel, MD, MPH and Morgan Grams, MD, PhD; co-mentor, Michelle Estrella, MD, MHS]. With resources provided by this award, Dr. Chen will develop proficiencies in study design, genetic and molecular epidemiology, and longitudinal data analysis related to CKD. Her proposed research project focuses on the role of immune activation in CKD progression and the interactive effects of immune activation with APOL1 risk variants. African Americans are disproportionately affected by CKD. This is in part due to the higher prevalence of APOL1 risk variants, genetic risk factors for kidney disease among individuals of African ancestry. The role of immune activation in the progression of non-diabetic CKD, particularly in APOL1 high-risk individuals, is unclear. The objectives of the proposed research are to: 1) study the associations of biomarkers of immune activation with CKD progression among non-diabetic African Americans with CKD attributed to hypertension; 2) determine whether the APOL1-associated risk for CKD progression is augmented by immune activation; 3) assess whether blood pressure interventions and dietary factors are associated with longitudinal changes in biomarkers of immune activation; 4) identify metabolomic predictors of biomarkers of immune activation. With over 10 years of follow-up, rigorously collected data, and stored biospecimens, the African American Study of Kidney Disease and Hypertension (AASK) represents an ideal cohort in which to study these potential associations. APOL1 genotyping and metabolomics measurements have previously been completed in AASK through other NIH-funded mechanisms. We propose to use stored serum samples from the baseline and 12- month visits of the trial phase to measure the following biomarkers of immune activation: tumor necrosis factor alpha (TNF-α), soluble TNF receptors 1 and 2 (sTNFR1 and sTNFR2), and interferon gamma (IFN-γ). The results of the proposed study will clarify the role of immune activation in CKD progression and perhaps identify novel targets for intervention. This could have important clinical implications in the treatment of African Americans with non-diabetic CKD, particularly among those with the APOL1 risk variants. The proposed research will also support Dr. Chen's long term-goal of transitioning towards an independent research career that ultimately improves the management and outcomes of African Americans with CKD. The rich training environment of Johns Hopkins University will ensure that she achieves these goals.

项目总结/摘要 特蕾莎·K Chen，医学博士，MHS是约翰霍普金斯大学肾脏科的助理教授 医学院。她正在申请K 08指导临床科学家研究职业发展 奖项，以获得必要的技能和指导研究经验，成为一个独立的 慢性肾脏病（CKD）领域的研究者。五年计划包括： 流行病学课程;生物标志物测量方面的实践经验; 经验丰富，致力于和多样化的导师团队[共同小学导师，劳伦斯阿佩尔， 医学博士，公共卫生硕士和摩根格拉姆，医学博士，博士;共同导师，米歇尔埃斯特雷拉，医学博士，MHS]。由以下机构提供资源： 该奖项，陈博士将发展在研究设计，遗传和分子流行病学， CKD相关的纵向数据分析。她提出的研究项目集中在免疫系统的作用， CKD进展中的免疫激活以及免疫激活与APOL 1风险变体的相互作用。 非裔美国人不成比例地受到CKD的影响。这部分是由于较高的流行率， APOL 1风险变异，非洲血统个体肾脏疾病的遗传风险因素的作用 非糖尿病CKD进展中的免疫激活，特别是在APOL 1高风险个体中， 不清楚本研究的主要目的是：1）研究免疫相关性生物标志物的相关性， 在患有高血压所致CKD的非糖尿病非洲裔美国人中，CKD进展的激活; 2） 确定免疫激活是否增加了CKD进展的APOL 1相关风险; 3） 评估血压干预和饮食因素是否与 免疫活化的生物标志物; 4）鉴定免疫活化的生物标志物的代谢组学预测因子。与 经过10多年的随访、严格收集的数据和储存的生物标本，非裔美国人研究发现， 肾脏疾病和高血压（AASK）是研究这些潜在风险的理想队列。 协会. APOL 1基因分型和代谢组学测量先前已在AASK完成 通过其他NIH资助的机制。我们建议使用基线和12- 在试验阶段的1个月访视，以测量以下免疫活化生物标志物：肿瘤坏死因子 α（TNF-α）、可溶性TNF受体1和2（sTNFR 1和sTNFR 2）和干扰素γ（IFN-γ）。 这项研究的结果将阐明免疫激活在CKD进展中的作用， 确定新的干预目标。这可能对治疗非洲的 患有非糖尿病CKD的美国人，特别是那些携带APOL 1风险变异的人。拟议 研究也将支持陈博士的长期目标，过渡到一个独立的研究生涯 最终改善非裔美国人慢性肾病患者的管理和结果。丰富的培训 约翰霍普金斯大学的环境将确保她实现这些目标。