Quantitative Genetics of Defective IgA1 Glycosylation in IgA Nephropathy

IgA 肾病 IgA1 糖基化缺陷的定量遗传学

• 批准号: 8245696
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 18.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-25 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245696
• 关键词: Antigen-Antibody Complex; B-Lymphocytes; Biological Assay; Biological Markers; Biometry; Candidate Disease Gene; Cell Line; Cells; Characteristics; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 10; Clinical; Complex; Data; Defect; Deposition; Detection; Development; Disease; Dominant Genes; Enzyme-Linked Immunosorbent Assay; Exhibits; Family; Family member; Fostering; Galactose; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genome; Genotype; Glomerulonephritis; Goals; Hand; Health; Hereditary Disease; Heritability; IgA1; Immunoglobulin A; In Vitro; Individual; Institution; Investigation; Kidney Diseases; Laboratories; Lectin; Maps; Mentors; Methods; Mutation; Nature; Participant; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Phenotype; Predisposition; Production; Quantitative Genetics; RNA Interference; Renal function; Risk; Role; Sampling; Scanning; Serum; Study of serum; Subgroup; Techniques; Testing; Tissue-Specific Gene Expression; Training; Transcript; Translational Research; Universities; Variant; base; career; cohort; effective therapy; endophenotype; ethnic difference; gene discovery; genetic analysis; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; genome-wide; glycosylation; knock-down; member; professor; segregation; skills; tool; trait

DESCRIPTION (provided by applicant): Krzysztof Kiryluk, Assistant Professor at Columbia University, is a clinical nephrologist with a formal training in biostatistics. His long-term goal is to develop an independent career conducting translational research in the genetics of IgA nephropathy and other forms of kidney disease. The purpose of this proposal is to foster his scientific development, laboratory skills, and build on his expertise in statistical genetics. IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Most IgAN patients exhibit a characteristic under-glycosylation of the IgA1 molecule. An increased serum level of galactose-deficient IgA1 (Gd-IgA1) is emerging as a useful biomarker of IgAN. Gd-IgA1 promotes formation and mesangial deposition of IgA1-containing immune complexes, but the reason why IgAN patients have high Gd-IgA1 is currently not known. Recently, a reliable lectin-based ELISA assay for detection of high levels of serum Gd-IgA1 has been developed. Krzysztof has utilized this assay to demonstrate that Gd-IgA1 levels are elevated in a large proportion of patients with IgAN and their family members as compared to unrelated controls. Moreover, Krzysztof conducted a whole-genome linkage scan for Gd-IgA1 in a large pedigree with familial IgAN and identified a major susceptibility locus on chromosome 10p14-15 (LOD=4.4). Based on these results, he hypothesizes that Gd-IgA1 level is, in part, genetically determined. He proposes to identify gene(s) responsible for high Gd-IgA1 levels by integration of linkage and gene expression data from this and other families with IgAN. In addition, he proposes to perform the first GWAS for Gd-IgA1 to identify possible contributions from common genetic variants to this phenotype. He will follow his findings by differential expression studies in IgA1-producing cells and in vitro functional studies of gene(s) contributing to abnormal glycosylation of IgA1. The proposed studies will be conducted in the laboratory of Dr. Gharavi (primary mentor), with Dr. Terwilliger (co-mentor) providing him with additional expertise in genetic analysis. Considering the inter-disciplinary nature of this project, Krzysztof has established a network of collaborators from different departments at Columbia University and outside institutions. Krzysztof's training plan builds on his strong background in applied biostatistics and statistical genetics. He will also obtain a "hands-on" training in laboratory methods. In the long term, Krzysztof hopes to build a highly productive independent laboratory to continue his scientific investigations in the field of complex disease genetics. PUBLIC HEALTH RELEVANCE: This project aims to discover the genes and pathways responsible for the abnormalities in IgA1 molecules that cause IgA nephropathy, the most common form of primary glomerulonephritis worldwide. The proposed studies of the genetic defects that result in the production abnormal IgA1 will lay the basis for the development of effective therapies for this serious disease.

描述（由申请人提供）：Krzysztof Kiryluk，哥伦比亚大学助理教授，是一位接受过生物统计学正规培训的临床肾脏病学家。他的长期目标是发展独立的职业生涯，开展 IgA 肾病和其他形式肾脏疾病遗传学的转化研究。该提案的目的是促进他的科学发展、实验室技能，并巩固他在统计遗传学方面的专业知识。 IgA 肾病 (IgAN) 是全世界原发性肾小球肾炎的最常见原因。大多数 IgAN 患者表现出 IgA1 分子糖基化不足的特征。半乳糖缺乏型 IgA1 (Gd-IgA1) 血清水平升高正在成为 IgAN 的有用生物标志物。 Gd-IgA1促进含有IgA1的免疫复合物的形成和系膜沉积，但IgAN患者具有高Gd-IgA1的原因目前尚不清楚。最近，开发了一种可靠的基于凝集素的 ELISA 测定法，用于检测高水平的血清 Gd-IgA1。 Krzysztof 利用该测定法证明，与无关对照相比，大部分 IgAN 患者及其家庭成员的 Gd-IgA1 水平升高。此外，Krzysztof 在一个具有家族性 IgAN 的大型家系中对 Gd-IgA1 进行了全基因组连锁扫描，并确定了染色体 10p14-15 上的一个主要易感位点（LOD=4.4）。根据这些结果，他推测 Gd-IgA1 水平部分是由基因决定的。他建议通过整合该家族和其他 IgAN 家族的连锁和基因表达数据来识别导致高 Gd-IgA1 水平的基因。此外，他建议对 Gd-IgA1 进行首次 GWAS，以确定常见遗传变异对该表型的可能贡献。他将通过 IgA1 产生细胞的差异表达研究以及导致 IgA1 糖基化异常的基因的体外功能研究来跟踪他的发现。拟议的研究将在 Gharavi 博士（主要导师）的实验室中进行，Terwilliger 博士（共同导师）为他提供基因分析方面的额外专业知识。考虑到该项目的跨学科性质，克日什托夫建立了一个来自哥伦比亚大学不同院系和外部机构的合作者网络。克日什托夫的培训计划建立在他在应用生物统计学和统计遗传学方面的深厚背景之上。他还将获得实验室方法的“实践”培训。从长远来看，克日什托夫希望建立一个高生产力的独立实验室，继续他在复杂疾病遗传学领域的科学研究。 公共健康相关性：该项目旨在发现导致 IgA 肾病（全球最常见的原发性肾小球肾炎）的 IgA1 分子异常的基因和途径。对导致 IgA1 产生异常的遗传缺陷的研究将为开发这种严重疾病的有效疗法奠定基础。