Immunogenetics of Common Polygenic Renal Disease

常见多基因肾病的免疫遗传学

基本信息

批准号：
10471535
负责人：
PETER A DORIS
金额：
$ 10万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471535
关键词：
Affect Animals Antibodies Antibody Formation Antigens Autoantibodies Bacteria Bacterial Translocation Blood Pressure Blood Vessels Chronic Kidney Failure Data Disease Disease susceptibility Genes Genetic Genetic Predisposition to Disease Genetic Variation Genetic study Genotype Heat-Shock Proteins 70 Homologous Gene Human Hypertension IGA Glomerulonephritis IGH@ gene cluster Immune system Immunogenetics Immunoglobulin G Immunoglobulins In Vitro Inbred SHR Rats Inbreeding Injury Injury to Kidney Kidney Diseases Kidney Transplantation Knock-out Lead Link Lupus Nephritis Lymphoid Tissue Maps Mediating Mediator of activation protein Membranous Glomerulonephritis Modeling Organ Orthologous Gene Pathogenesis Pathogenicity Pathway interactions Pharmacology Phenotype Population Predisposition Proteins Rat Strains Rattus Renal Hypertension Renal function Resistance Role Series Source Stress Structure Testing Variant Vascular Diseases Work allograft rejection commensal bacteria congenic design disorder risk experience genome wide association study gut bacteria human population genetics insight mesenteric lymphatics novel pressure tool

项目摘要

We seek to continue the remarkable series of insights that have emerged from our genetic studies in a rat model of hypertension-associated renal disease. This model acquires disease susceptibility from natural genetic variation. Our progress in uncovering and proving the causative genetic variation indicates that the final mediator of hypertensive renal injury is the genetically determined formation of pathogenic antibodies. While pathogenic antibodies have been implicated in rarer forms of kidney disease, they have not been implicated in human hypertensive disease, neither have they been excluded from such disease. In part, this may be because our work shows that genetic variation in the gene encoding immunoglobulin (IGH) makes a major contribution to disease risk. This large gene (1.2Mb in humans) contains extraordinary levels of structural diversity in both rats and humans. As a result, GWAS genotyping platforms drastically under-represent IGH variation and the presence of phenotypically important structural variation in IGH cannot be adequately considered. The rat model we use therefore, provides a tool to investigate the role of genetic variation in immunoglobulin in the pathogenesis of renal injury in hypertension that is not currently accessible in human population genetics. In the present study we will exploit inbred congenic hypertensive rat lines we have constructed to understand how genetic variation creates a pathogenic mechanism of disease. We will first seek out the source of antigens that elicit disease-causing antibodies. We have developed evidence of bacterial origin of these antigens and will investigate gut bacterial translocation. We will then investigate the target of pathogenic antibodies in order to link the alteration in renal function induced by elevated blood pressure with the emergence of disease in the presence of genetic susceptibility. We believe these studies can guide a pathway to explore and investigate analogous mechanisms of disease pathogenesis in humans.

我们寻求继续在高血压相关肾脏疾病的大鼠模型中我们的遗传研究中产生的一系列卓越的见解。该模型从自然遗传变异中获得疾病的敏感性。我们在发现和证明病因遗传变异方面的进展表明，高血压肾损伤的最终介体是致病性抗体的遗传确定形成。尽管致病性抗体与稀有形式的肾脏疾病有关，但它们没有与人类高血压疾病有关，也没有被排除在这种疾病之外。在某种程度上，这可能是因为我们的工作表明，编码免疫球蛋白（IGH）基因的遗传变异对疾病风险做出了重大贡献。这个大基因（人类中的1.2MB）都包含大鼠和人类的特殊水平。结果，GWAS基因分型平台在代表性不足的IGH差异和表型重要的IGH中的存在差异很大，因此无法充分考虑。因此，我们使用的大鼠模型提供了一种工具来研究遗传变异在人群遗传学中目前无法使用的高血压中肾脏损伤发病机理中遗传变异的作用。在本研究中，我们将利用我们已经构建的近交性高血压大鼠线，以了解遗传变异如何产生疾病的致病机制。我们将首先寻找引起致病抗体的抗原来源。我们已经开发了这些抗原的细菌来源的证据，并将研究肠道细菌易位。然后，我们将研究致病性抗体的靶标，以将血压升高的肾功能改变与存在遗传易感性的出现相结合。我们认为这些研究可以指导探索和研究人类疾病发病机理的类似机制的途径。