An Integrative Genomic Approach to APOL1-Associated Nephropathy.

APOL1 相关肾病的综合基因组方法。

基本信息

批准号：
8464696
负责人：
BARRY Ira FREEDMAN
金额：
$ 57.2万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464696
关键词：
22q13 22q13.1 AIDS-Associated Nephropathy Accounting Address Affect African African American African Trypanosomiasis American Angiotensin-Converting Enzyme Inhibitors Apolipoproteins Apoptosis Autophagocytosis Binding Biochemical Caucasians Caucasoid Race Cells Chromosomes Chronic Kidney Failure Code Communities Complex DNA Development Diagnosis Disease Disease Progression End stage renal failure Endothelial Cells Epithelial Cells European Exhibits Filtration Focal Segmental Glomerulosclerosis Frequencies Functional disorder Gene Cluster Gene Expression Gene Frequency Genes Genetic Genetic Variation Genomics Genotype Grant HIV High Density Lipoproteins Histologic Human Hypertension In Vitro Incidence Individual Inherited Kidney Kidney Diseases Lead Linkage Disequilibrium Lipids Lipoprotein Binding Lipoproteins Mediating Messenger RNA Metabolism Modeling Modification Molecular Genetics Molecular Profiling Mus Myosin Heavy Chains Nephrectomy Odds Ratio Parasites Pathogenesis Pathway interactions Patients Pattern Plasma Proteins Public Health RNA Splicing Recombinants Relative (related person)Risk Risk Factors Rodent Rosa Scientist Signal Transduction Sleep Tissues Toxic effect Transcript Transgenic Mice Transgenic Organisms Trypanosoma brucei brucei Variant Work base blood pressure regulation cell type deep sequencing design disorder risk effective therapy gene discovery high density lipoprotein receptor hypertension control improved in vivo kidney cell killings nephrotoxicity non-diabetic non-muscle myosin novel particle podocyte prevent protein expression racial difference receptor binding repository research study risk variant secretory protein

项目摘要

DESCRIPTION (provided by applicant): The incidence rates of common forms of kidney disease including that attributed to hypertension are significantly higher in African Americans, relative to Caucasians. Racial differences in the frequency of Apolipoprotein L1 gene (APOL1) variants are now known to account for these differences. APOL1 risk variants rose to high frequency in African Americans since one copy protects from the parasite that causes African sleeping sickness, a potentially fatal disease. Approximately 10% of African Americans inherit two copies of APOL1 risk variants, placing them at a ten-fold increased risk for kidney disease. The mechanism whereby APOL1 gene variants contribute to kidney disease is unknown. This application proposes to determine how APOL1 gene variants contribute to kidney disease, information likely to yield more effective therapies. Existing therapies including strict blood pressure control have had disappointing results. We propose to determine whether: (1) variation in the APOL1 gene in kidney cells directly leads to cell dysfunction with resultant kidney disease, and/or (2) abnormal circulating ApoL1 proteins (high density lipoprotein [HDL] bound or lipid-free) lead to kidney disease. To explore mechanism 1, gene expression profiles will be examined in kidney cells from African Americans with and without APOL1 risk variants to determine which genes and gene pathways are over expressed (turned up) or under expressed (turned down), based upon the APOL1- specific genetic make-up of the cells. To explore mechanism 2, the amount and binding patterns of circulating ApoL1 proteins to HDL will be examined based upon an individual's genetic make- up. Kidney cells will be exposed to normal and risk ApoL1 proteins in vitro to determine whether risk variant proteins are toxic to cells and how this toxicity manifests. Based on these studies, additional analyses may be conducted in transgenic mice expressing normal and variant APOL1 to assess renal effects and in vivo metabolism of ApoL1 proteins. We will also attempt to identify undetected kidney disease risk variants in the APOL1 gene by deeply sequencing the surrounding chromosomal region. These experiments are likely to determine the mechanisms whereby APOL1 gene variants lead to non-diabetic kidney disease and assist in finding a cure for this devastating disease disproportionately impacting the African American community.

描述（由申请人提供）：与白种人相比，非洲裔美国人常见肾脏疾病（包括高血压引起的肾脏疾病）的发病率明显更高。现在已知载脂蛋白 L1 基因 (APOL1) 变异频率的种族差异是造成这些差异的原因。 APOL1 风险变异在非裔美国人中出现的频率很高，因为其中一个拷贝可以防止导致非洲昏睡病（一种潜在致命疾病）的寄生虫。大约 10% 的非裔美国人遗传了两个 APOL1 风险变异拷贝，使他们患肾脏疾病的风险增加了十倍。 APOL1 基因变异导致肾脏疾病的机制尚不清楚。该应用旨在确定 APOL1 基因变异如何导致肾脏疾病，这些信息可能会产生更有效的治疗方法。包括严格血压控制在内的现有疗法的结果令人失望。我们建议确定是否：(1) 肾细胞中 APOL1 基因的变异直接导致细胞功能障碍，从而导致肾脏疾病，和/或 (2) 异常循环 ApoL1 蛋白（高密度脂蛋白 [HDL] 结合或无脂）导致肾脏疾病。为了探索机制 1，将对具有和不具有 APOL1 风险变异的非裔美国人的肾细胞中的基因表达谱进行检查，根据 APOL1- 确定哪些基因和基因通路过度表达（上调）或表达不足（下调）。细胞的特定遗传组成。为了探索机制 2，将根据个体的基因组成检查循环 ApoL1 蛋白与 HDL 的数量和结合模式。肾细胞将在体外暴露于正常和风险 ApoL1 蛋白，以确定风险变异蛋白是否对细胞有毒以及这种毒性如何表现。基于这些研究，可以在表达正常和变异 APOL1 的转基因小鼠中进行额外的分析，以评估 ApoL1 蛋白的肾效应和体内代谢。我们还将尝试通过对周围染色体区域进行深度测序来识别 APOL1 基因中未检测到的肾脏疾病风险变异。这些实验可能会确定 APOL1 基因变异导致非糖尿病肾病的机制，并有助于找到治疗这种严重影响非裔美国人社区的毁灭性疾病的方法。