JAK-STAT Inhibition to Reduce Racial Disparities in Kidney Disease

项目摘要 与白色美国人相比，美国黑人受肾脏疾病进展的影响不成比例。 载脂蛋白L1（APOL 1）基因突变与肾脏疾病的种族/民族差异有关。 健康然而，并非所有携带高风险APOL 1变异的个体都会发生肾衰竭。心理社会 压力，通常在美国黑人中报道，可能是一个潜在的恶化因素， 通过炎症和刺激交感神经系统增加肾脏疾病的风险。 这一建议的中心假设是，累积的生活压力与以下因素的失调有关： 多个生理系统，有利于APOL 1相关肾病的发展。 在一项前瞻性研究中，这项建议将调查累积的生活压力与 南方黑人患者的生理过程失调。AIM 1A将评估是否 居住在南方的非洲血统的患者，累积生活压力高， 与低累积生活压力患者相比，炎症标志物和血压水平; Aim 1B 将评估非洲血统的南方居民患者与高血压患者之间的相互作用， 累积的生活压力和高风险的APOL 1基因型与较高水平的炎症标志物相关 血压升高目的2A将评估非洲血统的南方居住患者是否 高水平的压力将有较高的患病率肾功能不全，表现为白蛋白尿≥ 20 mg/g eGFR <75 ml/min/1.73m2，与低水平累积生活压力的人相比;目标2B将 评估非洲血统的南方居民患者与高累积 生活压力和高风险APOL 1基因型与南方居民肾功能不全相关 非洲血统的患者。利用社区APOL 1研究参与队列，我们将 通过招募400名居住在南方的黑人患者并进行交叉研究， 对累积生活压力与炎症、血压升高、 和肾功能障碍我们还将评估APOL 1高风险变异如何改变上述基因， 累积的生活压力和我们感兴趣的结果之间的关系。 执行本提案中概述的这些科学目标和职业发展活动， 导师团队，将定位卢卡斯博士建立自己作为一个成功的初级研究员对未来 指导以病人为导向的研究职业发展奖（K23），重点是心理社会压力， 美国黑人肾病

Project Summary Black Americans are disproportionately affected by kidney disease progression compared to White Americans. Mutations in the Apolipoprotein L1 (APOL1) gene have been implicated in this racial/ethnic disparity in kidney health. However, not all individuals who carry high risk APOL1 variants develop kidney failure. Psychosocial stress, commonly reported among Black Americans, may serve as a potential exacerbating factor which may increase the risk of kidney disease through inflammation and stimulation of the sympathetic nervous system. The central hypothesis of this proposal is that cumulative life stress is associated with the dysregulation of multiple physiological systems, favoring the development of APOL1 associated kidney disease. In a prospective study, this proposal will investigate the association between cumulative life stress and dysregulation of physiologic processes among Southern-dwelling Black patients. Aim1A will evaluate whether Southern-dwelling patients of African ancestry with high levels of cumulative life stress will experience higher levels of inflammatory markers and blood pressure compared to patients with low cumulative life stress; Aim1B will evaluate whether an interaction between Southern-dwelling patients of African ancestry with high cumulative life stress and a high risk APOL1 genotype is associated with higher levels of inflammatory markers and elevated blood pressure. Aim 2A will evaluate whether Southern-dwelling patients of African ancestry with high levels of stress will have a higher prevalence of kidney dysfunction, manifested by albuminuria ≥20mg/g and reduced eGFR <75ml/min/1.73m2, compared to those with low levels of cumulative life stress; Aim 2B will evaluate whether an interaction between Southern-dwelling patients of African ancestry with high cumulative life stress and high risk APOL1 genotype is associated with kidney dysfunction among Southern-dwelling patients of African ancestry. Leveraging the Community APOL1 research Engagement cohort, we will accomplish these proposed aims by enrolling 400 Southern-dwelling Black patients and conducting a cross- sectional analysis of the relationship between cumulative life stress and inflammation, elevated blood pressure, and kidney dysfunction. We will also evaluate how APOL1 high risk variant modifies the aforementioned relationships between cumulative life stress and our outcomes of interest. Execution of these scientific aims and career development activities outlined in this proposal, and a strong mentorship team, will position Dr. Lucas to establish herself as a successful junior investigator on a future mentored patient-oriented research career development award (K23) focused on psychosocial stress and kidney disease among Black Americans.