Focal Segmental Glomerulosclerosis: Genetics & Mechanisms

局灶节段性肾小球硬化：遗传学

• 批准号: 8939574
• 负责人: Jeffrey Burnett Kopp
• 金额: $ 58.34万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939574
• 关键词: Affect; African; African American; Albuminuria; Aryl Hydrocarbon Receptor; Autopsy; Body mass index; Chromosomes, Human, Pair 22; Cicatrix; Clinical; Cyclosporine; Disease; Family; Focal Segmental Glomerulosclerosis; Gene Mutation; Genes; Genetic; Genetic Variation; Genome Scan; HIV; Heart; Hyperplasia; Hypertrophy; In Vitro; Incidence; Indican; Individual; Keloid; Kidney; Kidney Diseases; Kidney Transplantation; Left Ventricular Hypertrophy; Ligands; Lipids; Mississippi; Mus; Mycophenolate; Obesity; Pathologic; Phenotype; Platelet Factor 4; Pre-Eclampsia; Proteins; Recurrence; Renal Mass; Risk; Scanning; Sickle Cell; Sickle Cell Anemia; Syndrome; Toxin; Variant; cohort; exome; in vivo; injured; macrophage; particle; podocyte; renal toxin; response; risk variant

Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic. The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. In prior years, we have shown that most of this effect is due to genetic variation in MYH9 and APOL1, adjacent genes on chromosome 22. A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus. An exome scan has identified several promising candidate loci which we are further characterizing. chip. Our progress during the past year included the following: - Showing in CARDIA that APOL1 risk alleles are associated with albuminuria and reduced eGFR (JAMA, revision under review) - Analysis of a Mississippi autopsy cohort to show that African Americans with two APOL1 risk alleles have, with larger body mass index, for larger glomeruli, larger kidneys and larger hearts, suggesting that left ventricular hypertrophy might be an APOL1 risk allele phenotype (Kidney Int, under review) - Showing that APOL1 variants do not affect response to mycophenolate or cyclosporine (Kopp, JASN, in press) - Showing that indoxyl sulfate, a uremic toxin and a ligand for the dioxin receptor (Ahr), injures podocytes in vivo and in vitro (Ichii, PLOS One, in press) Current projects - extension to other kidney diseases, including sickle cell nephropathy, pre-eclampsia, and renal transplantation - characterization of APOL1 lipid profiles including particle number and macrophage function in healthy volunteerrs - have generated Alb/APOL1 mice that express circulating ApoL1 and are characterizing the mice

局灶性节段性肾小球硬化症（FSGS）是一种临床病理综合征，其特征是纤维化蛋白在肾小球中的积累，最初仅涉及一些肾小球（局灶性），并且涉及受影响的肾小球的部分（段）。 FSG可以分类如下：特发性FSG，遗传FSG和自适应后FSG（与肾小球肥大和过滤相关，以及肾脏质量，肾脏毒素，肥胖症和镰状细胞病）。相关的综合征崩溃的肾小球病，与足细胞增生有关，而FSGS与足细胞耗竭有关。崩溃的肾小球病可以归类为与HIV相关或特发性。 在非洲裔美国人中，特发性FSG的发生率增加了4倍，与艾滋病毒相关的崩溃肾小球的发生率在非裔美国人中增加了18倍。在过去的几年中，我们已经表明，大多数这种作用是由于MYH9和APOL1的遗传变异引起的，这是22号染色体上的邻近基因。 一个相关的项目探讨了假设在非洲血统个体中更常见的其他疤痕疾病与基因突变有关。 我们已经确定了许多具有家族性乳突的不同地理祖先的家庭，并将使用基因组扫描来识别负责任的基因座。 外显子扫描已经确定了几个有前途的候选基因座，我们正在进一步表征。 芯片。 过去一年中，我们的进度包括以下内容： - 在Cardia中表明APOL1风险等位基因与蛋白尿和减少EGFR相关（JAMA，正在审查） - 对密西西比州尸检队列的分析表明，具有两个APOL1风险等位基因的非洲裔美国人具有较大的体重指数，用于较大的肾小球，较大的肾脏和更大的心脏，这表明左心室肥大可能是ApoL1风险的风险等位基因（肾脏Int，审查） - 表明apol1变体不影响对霉菌酸盐或环孢菌素的反应（Kopp，Jasn，印刷中） - 表明硫酸硫酸盐，尿毒症毒素和一种用于二恶英受体（AHR）的配体，体内损伤足细胞和体外（ICHII，PLOS ONE，PRASS） 当前项目 - 延伸到其他肾脏疾病，包括镰状细胞肾病，前球和肾移植 - 在健康志愿者中的Apol1脂质曲线的表征包括颗粒数和巨噬细胞功能 - 已经产生了表达循环apol1并表征小鼠的Alb/apol1小鼠