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.

我们寻求继续我们在高血压相关肾病大鼠模型中进行的基因研究中得出的一系列引人注目的见解。该模型从自然遗传变异中获得疾病易感性。我们在揭示和证明致病性遗传变异方面取得的进展表明，高血压肾损伤的最终介质是基因决定的致病性抗体的形成。虽然致病性抗体与较罕见的肾脏疾病有关，但它们并未与人类高血压疾病有关，也没有被排除在此类疾病之外。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) 的基因的遗传变异对疾病风险起着重要作用。这个大基因（在人类中为 1.2Mb）在大鼠和人类中都包含非凡水平的结构多样性。因此，GWAS 基因分型平台极大地低估了 IGH 变异，并且无法充分考虑 IGH 中表型重要的结构变异的存在。因此，我们使用的大鼠模型提供了一种工具来研究免疫球蛋白遗传变异在高血压肾损伤发病机制中的作用，目前在人类群体遗传学中尚无法实现。在本研究中，我们将利用我们构建的近交同源高血压大鼠系来了解遗传变异如何产生疾病的致病机制。我们将首先寻找引发致病抗体的抗原来源。我们已经开发出这些抗原的细菌起源的证据，并将研究肠道细菌易位。然后，我们将研究致病性抗体的目标，以便将血压升高引起的肾功能改变与遗传易感性存在的疾病的出现联系起来。我们相信这些研究可以指导探索和研究人类疾病发病机制的类似机制。