Hypertensive Renal Injury

高血压肾损伤

基本信息

批准号：
8692749
负责人：
PETER A DORIS
金额：
$ 45.87万
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：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692749
关键词：
Affect Albuminuria American Animals Beryllium Blood Pressure Chromosome Mapping Chromosomes, Human, Pair 14 Chromosomes, Human, Pair 17 Critiques DNA Diabetes Mellitus Dialysis procedure Disease Disease susceptibility Elements Evolution Funding Genes Genetic Genetic Models Genetic Variation Genome Heavy-Chain Immunoglobulins Heritability Host Defense Human Hypertension IGH@ gene cluster Immunoglobulin G Inbreeding Individual Injury Kidney Kidney Diseases Kidney Failure Lead Life Life Expectancy Maps Measures Metabolism Modeling Mothers Organ Pathology Pathway interactions Population Predisposition Quantitative Trait Loci Rattus Relative (related person)Renal function Risk Rodent Secondary to Single Nucleotide Polymorphism Map Staging Structure Tissues Translating Transplantation Variant Work blood pressure regulation human population genetics immune function interest novel strategies offspring pathogen public health relevance response trait transmission process

项目摘要

DESCRIPTION (provided by applicant): In the prior funding period we have introduced a new approach to genetic mapping in inbred rodent strains that exploits closely related lines differing in traits of interest. Using a 10K SNP map, we have shown that two SHR lines differ at only 13% of their genomes, but that these differences have a profound effect on susceptibility to hypertensive renal disease. The close genetic similarity has allowed us to perform fine mapping that has resulted in the identification of three highly resolved quantitative trait loci (QTL) affecting blood pressure and renal injury. Because of the similarity between the lines, each of these QTL maps to a small, isolated block where the two SHR lines have descended from different ancestors. These blocks are surrounded by extensive regions that are identical-by-descent (IBD) and thus help to narrowly define the QTL's, down to a small number of genes. In the present study we propose to identify the genes in each QTL that contribute to increased hypertensive renal disease and to understand the mechanisms by which they act. One QTL has effects on both blood pressure and renal injury. We seek to identify the causative variation and determine whether it acts first on blood pressure with secondary effects on injury or whether it lies in a pathway that produces injury that then leads to reduced renal function and increased blood pressure. Another QTL has no effect on blood pressure and appears to lead to glomerular damage directly. We have also identified the immunoglobulin heavy chain as a locus containing extensive variation across our lines. We have shown that this includes variation with important effects on IgG function including the inability to transfer IgG from mother to offspring. This variation associates with increased albuminuria. We propose to investigate whether alterations in immune function that are encoded by differences in the heavy chain of immunoglobulin contribute to the emergence of renal disease in the susceptible SHR line and whether maternal-offspring IgG transfer is involved in the transmission of risk. We have identified allelic variatio in IgG in humans that is widespread and ancient and that is functionally homologous to the variation we detected across SHR lines. We will perform a large-scale human population genetic study to determine the association of this variation with renal function in humans.

描述（由申请人提供）：在之前的资助期间，我们引入了一种近交啮齿动物品系遗传图谱的新方法，该方法利用了具有不同兴趣特征的密切相关品系。使用 10K SNP 图谱，我们发现两个 SHR 系的基因组仅存在 13% 的差异，但这些差异对高血压肾病的易感性具有深远的影响。密切的遗传相似性使我们能够进行精细定位，从而鉴定出影响血压和肾损伤的三个高度解析的数量性状基因座（QTL）。由于品系之间的相似性，这些 QTL 中的每一个都映射到一个小的、孤立的块，其中两个 SHR 品系来自不同的祖先。这些块被广泛的血统相同 (IBD) 区域包围，因此有助于狭义地定义 QTL，直至少量基因。在本研究中，我们建议鉴定每个 QTL 中导致高血压肾病增加的基因，并了解它们的作用机制。一个QTL对血压和肾损伤都有影响。我们试图找出致病变异，并确定它是否首先作用于血压并对损伤产生次要影响，或者它是否存在于产生损伤的途径中，从而导致肾功能下降和血压升高。另一个QTL对血压没有影响，似乎直接导致肾小球损伤。我们还鉴定出免疫球蛋白重链是一个在我们的品系中包含广泛变异的基因座。我们已经证明，这包括对 IgG 功能产生重要影响的变异，包括无法将 IgG 从母亲转移到后代。这种变化与白蛋白尿增加有关。我们打算研究免疫球蛋白重链差异编码的免疫功能改变是否导致易感 SHR 系中肾病的出现，以及母子 IgG 转移是否参与风险传播。我们已经鉴定出人类 IgG 中广泛存在且古老的等位基因变异，并且与我们在 SHR 系中检测到的变异在功能上同源。我们将进行大规模的人群遗传学研究，以确定这种变异与人类肾功能的关联。