Biomarkers of Immune Activation in African Americans with CKD

项目摘要/摘要 Teresa K.Chen，医学博士，医学硕士，约翰霍普金斯大学肾病学系助理教授 医学院。她正在申请K08临床科学家指导研究职业发展 奖励，以获得必要的技能和指导的研究经验，成为一个独立的 慢性肾脏病(CKD)领域的研究员。拟议的五年计划包括先进的 流行病学课程；生物标志物测量的实际经验；以及 非常有经验、投入和多样化的导师团队[联合小学导师，劳伦斯·阿佩尔， 医学博士、公共卫生硕士和摩根·格拉姆斯，医学博士，博士；共同导师，米歇尔·埃斯特雷拉，医学博士，医学硕士。由以下机构提供资源 在这个奖项中，陈博士将精通研究设计、遗传学和分子流行病学，以及 与CKD相关的纵向数据分析。她提出的研究项目侧重于免疫的作用。 慢性肾脏病进展中的激活以及免疫激活与APOL1风险变异体的交互作用。 非裔美国人受到CKD的影响不成比例。这在一定程度上是由于较高的发病率 APOL1风险变异体，非洲血统个体中肾脏疾病的遗传风险因素。的作用 免疫激活在非糖尿病CKD的进展中，特别是在APOL1高危个体中是 不清楚。本研究的目的是：1)研究免疫相关生物标志物之间的关系。 非糖尿病非裔美国人中因高血压导致的慢性肾脏病的激活与慢性肾脏病进展有关；2) 确定CKD进展的APOL1相关风险是否因免疫激活而增加；3) 评估血压干预和饮食因素是否与以下方面的纵向变化有关 免疫激活的生物标志物；4)确定免疫激活的生物标志物的代谢预测因子。使用 经过10多年的跟踪调查，严格收集数据并存储生物标本，非裔美国人研究 肾脏疾病和高血压(AASK)是研究这些潜力的理想队列 联想。APOL1基因分型和代谢组学测量之前已经在AASK完成 通过美国国立卫生研究院资助的其他机制。我们建议使用基线存储的血清样本和12- 试验阶段每月访问以测量以下免疫激活的生物标志物：肿瘤坏死因子 α(肿瘤坏死因子-α)、可溶性肿瘤坏死因子受体1和2(sTNFR 1和sTNFR 2)、干扰素-γ。 拟议的研究结果将阐明免疫激活在慢性肾脏病进展中的作用，并可能 确定新的干预目标。这可能对非洲人的治疗具有重要的临床意义。 患有非糖尿病慢性肾脏病的美国人，特别是那些具有APOL1风险变异的人。建议数 研究还将支持陈博士向独立研究生涯过渡的长期目标 这最终改善了患有慢性肾脏病的非裔美国人的管理和结果。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。

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.