APOL1 associated disease spectrum

APOL1相关疾病谱

基本信息

批准号：
10683097
负责人：
KATALIN SUSZTAK
金额：
$ 53.09万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-21 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683097
关键词：
Adhesions Adult Affect African American African American population African Trypanosomiasis Albuminuria American Apolipoproteins Autophagocytosis Blood Coagulation Disorders Cell Adhesion Molecules Cells Coagulation Process Code Defect Development Disease Endocytosis Endothelial Cells Endothelium European Extravasation First Independent Research Support and Transition Awards Functional disorder Gene Expression Genes Genetic Genetic Models Genotype Glycocalyx Hepatocyte Hospitals Human In Situ Hybridization Incidence Inflammasome Inflammation Inflammatory Interferons Kidney Kidney Diseases Link Lipopolysaccharides Mitochondrial DNA Modeling Molecular Mus Nucleotides Organ Parasites Pathology Pathway interactions Patients Permeability Persons Plasma Predisposition Resistance Risk Role Sepsis Severities Study models Transgenic Mice Trypanosoma Variant Vascular Permeabilities Virus Diseases biobank cecal ligation puncture cell type cohort cytokine disorder risk epigenome genetic selection glomerulosclerosis health determinants health disparity high risk hospitalization rates in vivo inducible gene expression kidney cell mortality mouse model novel therapeutics pharmacologic podocyte risk variant trafficking transcriptome

项目摘要

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

每年，美国至少有170万成年人出现败血症，近270,000名美国人死亡败血症。在医院死亡的3例中有1例患有败血症。非洲裔美国人的重度高67％败血症住院率，即使调整后，与白人相比，败血症死亡的可能性高20％共同变化。接近45％的非裔美国人至少携带一个Apol1风险等位基因。考虑到apol1中的变体由于阳性遗传选择而产生的，因为它们赋予对锥虫的抗性罗德西森（Rhodesiense），一种寄生虫，会引起非洲睡眠。有一个风险变体赋予这种关键抵抗睡眠疾病，有两个风险等位基因可显着增加患肾脏的风险疾病。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）可能解释非洲裔美国人的败血症易感性和严重程度的增加。 AIM1。定义RV Apol1在小鼠模型和患者中的作用。 A.败血症的严重程度在内皮细胞中有条件诱导表达和参考apol1的小鼠中，肾脏和肝脏细胞。 B.检查Apol1 RV基因型与败血症发生率与严重程度之间的关联 Upenn（PMBB）和Vanderbilt（Biovu）生物库。 C.确定等离子体APOL1水平的关联和梅西队列中的败血症严重程度。 AIM2。定义内皮RV APOL1诱导的病理学。答：rvapol1内皮病的特征随着炎症，使用ISEGENIC基因编辑的RV APOL1人类和小鼠转基因内皮细胞。 B.使用单细胞基因表达表征与 RV APOL1引起的体内内皮病。 C.描述RV Apol1诱导的细胞运输缺陷例如EC中的内吞作用，自噬和线粒体。 AIM3。确定炎症体的药理或细胞类型特异性遗传靶向（NLRP3）和核苷酸传感途径（STING）减轻了内皮RV APOL1相关的内皮RV 内皮病和败血症 RV APOL1是影响美国数百万人的健康差异的关键决定因素。我们的研究愿意定义败血症中RV APOL1的内皮作用，并可以鉴定出靶向RV Apol1