APOL1 associated disease spectrum

每年，美国至少有170万成年人患上败血症，近27万美国人死于 败血症。在医院死亡的患者中，每3人中就有1人患有败血症。非裔美国人的严重程度要高67% 脓毒症住院率和死于脓毒症的可能性比白人高20% 协变量。近45%的非裔美国人至少携带一个APOL1风险等位基因。APOL1中的变体被认为 作为正向遗传选择的结果，它们对布鲁氏锥虫具有抵抗力 一种引起非洲昏睡病的寄生虫。虽然有一个风险变量可以提供至关重要的 对昏睡病的抵抗力，拥有两个风险等位基因会显著增加肾脏发育的风险 疾病。 最近的遗传学和小鼠模型研究表明，内皮细胞中的APOL1风险变量(RV)可能 解释非裔美国人败血症易感性和严重性增加的原因。 目的：1.明确RV APOL1在小鼠模型和患者脓毒症中的作用。A.描述脓毒症的严重程度 RV和参考APOL1在血管内皮细胞、肾脏和肝脏条件诱导表达的小鼠 细胞。B.检查APOL1 RV基因与脓毒症发病率和严重程度之间的关系 宾夕法尼亚大学(UPenn)和范德比尔特大学(Vanderbilt)生物库。C.确定血浆载脂蛋白1水平与 梅西队列中的脓毒症严重程度。 AIM2.定义内皮细胞RV APOL1诱导的病理。A.描述RVAPOL1内皮病的特征 由于炎症、通透性和凝血功能的改变，使用同基因编辑的RV APOL1人和 转基因小鼠内皮细胞。B.使用单细胞基因表达来表征与 RV APOL1诱导的活体内皮病变。C.描述轮状病毒APOL1引起的细胞转运缺陷 如EC的内吞作用、自噬和有丝分裂吞噬。 Aim3.确定炎症体的药理学或细胞类型特异性基因靶向 (NLRP3)和核苷酸感觉通路(STING)缓解内皮细胞RV APOL1相关 内皮病与脓毒症 RV APOL1是影响美国数百万人健康差距的关键决定因素。我们的研究将 明确RV APOL1在脓毒症中的内皮作用，并可寻找靶向RV APOL1的新药

Each year, at least 1.7 million adults in the US develop sepsis and nearly 270,000 Americans die of sepsis. 1 in 3 patients who dies in a hospital has sepsis. African Americans have a 67% higher severe sepsis hospitalization rate and 20% more likely to die of sepsis compared to whites even after adjusting for co-variates. Close to 45% African American carry at least one APOL1 risk allele. Variants in APOL1 are thought to have arisen as a result of positive genetic selection, as they confer resistance against Trypanosome brucei rhodesiense, a parasite that causes African sleeping sickness. While having one risk variant imparts this crucial resistance against sleeping sickness, having two risk alleles significantly increases the risk of developing kidney disease. Recent genetic and mouse model studies indicate that APOL1 risk variant (RV) in endothelial cells might explain the increased sepsis susceptibility and severity in African Americans. Aim1. Define the role of RV APOL1 in sepsis in mouse models and patients. A. Characterize sepsis severity in mice with conditional inducible expression of RV and reference APOL1 in endothelial cells, kidney and liver cells. B. Examine the association between APOL1 RV genotype and sepsis incidence and severity in the Upenn (PMBB) and Vanderbilt (BioVU) Biobanks. C. Determine the association of plasma APOL1 level and sepsis severity in the MESSI cohort. Aim2. Define endothelial RV APOL1 induced pathology. A. Characterize RVAPOL1 endotheliopathy such as inflammation, permeability and coagulation changes using isogenic gene edited RV APOL1 human and mouse transgenic endothelial cells. B. Using single cell gene expression characterize changes associated with RV APOL1-induced endotheliopathy in vivo. C. Describe the cellular trafficking defect induced by RV APOL1 such as endocytosis, autophagy, and mitophagy in EC. Aim3. Determine whether pharmacological, or cell type specific genetic targeting of the inflammasome (NLRP3) and nucleotide sensing pathways (STING) alleviate endothelial RV APOL1 associated endotheliopathy and sepsis RV APOL1 is a critical determinant of health disparities affecting millions of people in the US. Our study will define the role endothelial of RV APOL1 in sepsis and could identify novel drugs to target RV APOL1