APOL1 associated disease spectrum

每年，美国至少有170万成年人患败血症，近27万美国人死于败血症。 败血症在医院死亡的三分之一的患者患有败血症。非裔美国人有67%的严重 脓毒症住院率和20%更可能死于脓毒症相比，白人，即使调整后， 协变量近45%的非洲裔美国人携带至少一个APOL1风险等位基因。APOL1的变异体被认为是 是积极遗传选择的结果，因为它们赋予了对布氏锥虫的抗性 罗得西亚，一种导致非洲昏睡病的寄生虫。虽然有一个风险变量赋予这一关键 抵抗昏睡病，有两个风险等位基因显着增加发展肾脏的风险 疾病 最近的遗传和小鼠模型研究表明，内皮细胞中的APOL1风险变体（RV）可能 解释了非裔美国人败血症易感性和严重程度的增加。 目标1.定义RV APOL 1在小鼠模型和患者脓毒症中的作用。A.描述脓毒症严重程度 在内皮细胞、肾脏和肝脏中RV和参比APOL 1条件诱导表达的小鼠中 细胞B。研究APOL1 RV基因型与脓毒症发病率和严重程度之间的关系， Upenn（PMBB）和范德比尔特（BioVU）生物样本库。C.确定血浆APOL 1水平与 MESSI队列中的脓毒症严重程度。 目标2。定义内皮RV APOL 1诱导的病理学。A.表征RVAPOL 1内皮病， 作为炎症，渗透性和凝血变化，使用同基因编辑的RV APOL 1人和 小鼠转基因内皮细胞。B。使用单细胞基因表达表征与 RV APOL 1诱导的体内内皮病变。C.描述RV APOL 1诱导的细胞运输缺陷 如内吞、自噬和线粒体自噬等。 目标3。确定炎性小体的药理学或细胞类型特异性遗传靶向 NLRP3和核苷酸传感途径（STING）缓解了内皮RV APOL 1相关性 内皮病和脓毒症 RV APOL 1是影响美国数百万人健康差异的关键决定因素。我们的研究将 明确RV APOL 1在脓毒症中的内皮作用，并可鉴定靶向RV APOL 1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