Hypertensive Renal Injury

高血压肾损伤

• 批准号: 8494186
• 负责人: PETER A DORIS
• 金额: $ 49.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/8494186
• 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

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）：在前一个资助期内，我们引入了一种新的方法，利用密切相关的品系在感兴趣的性状不同的近交啮齿动物品系的遗传图谱。使用10 K SNP图谱，我们已经表明，两个SHR品系的差异只有13%的基因组，但这些差异对高血压肾病的易感性有深远的影响。密切的遗传相似性，使我们能够进行精细的定位，导致在三个高分辨率的数量性状基因座（QTL）影响血压和肾损伤的鉴定。由于品系之间的相似性，这些QTL中的每一个都定位到一个小的、孤立的区块，其中两个SHR品系来自不同的祖先。这些块被广泛的区域所包围，这些区域是血统相同的（IBD），因此有助于狭义地定义QTL，直到少量的基因。在本研究中，我们建议确定每个QTL中的基因，有助于增加高血压肾病，并了解其作用机制。一个QTL对血压和肾损伤都有影响。我们试图确定致病变异，并确定它是否首先作用于血压，对损伤产生继发性影响，或者它是否位于产生损伤的途径中，然后导致肾功能降低和血压升高。另一个QTL对血压没有影响，似乎直接导致肾小球损伤。我们还将免疫球蛋白重链鉴定为在我们的品系中含有广泛变异的基因座。我们已经表明，这包括对IgG功能具有重要影响的变化，包括无法将IgG从母亲转移到后代。这种变化与蛋白尿增加有关。我们建议调查是否在免疫功能的变化，编码的免疫球蛋白重链的差异，导致肾脏疾病的出现在易感的SHR线，以及是否母-子代IgG转移参与风险的传递。我们已经鉴定了人类IgG中广泛存在的古老的等位基因变异，并且与我们在SHR品系中检测到的变异在功能上同源。我们将进行一项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。