JAK-STAT Inhibition to Reduce Racial Disparities in Kidney Disease

点击翻译按钮获取中文摘要

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.