Quantitative Genetics of Defective IgA1 Glycosylation in IgA Nephropathy

描述（由申请人提供）：哥伦比亚大学助理教授Krzysztof Kiryluk是一名临床肾病学家，接受过生物统计学的正式培训。他的长期目标是发展一个独立的职业生涯，在伊加肾病和其他形式的肾脏疾病的遗传学方面进行转化研究。这项建议的目的是促进他的科学发展，实验室技能，并建立在他的专业知识在统计遗传学。伊加肾病（IgAN）是世界范围内原发性肾小球肾炎最常见的病因。大多数IgAN患者表现出特征性的IgA 1分子糖基化不足。半乳糖缺陷型IgA 1（Gd-IgA 1）血清水平升高是IgA肾病的一个有用的生物标志物。Gd-IgA 1促进含IgA 1免疫复合物的形成和系膜沉积，但IgAN患者具有高Gd-IgA 1的原因目前尚不清楚。最近，一个可靠的凝集素为基础的ELISA检测高水平的血清Gd-IgA 1已经开发出来。Krzysztof利用该测定证明，与无关对照相比，大部分IgAN患者及其家庭成员的Gd-IgA 1水平升高。此外，Krzysztof在一个家族性IgAN大家系中进行了Gd-IgA 1的全基因组连锁扫描，并在染色体10 p14 -15上确定了一个主要易感位点（LOD=4.4）。基于这些结果，他假设Gd-IgA 1水平部分由遗传决定。他建议通过整合来自该家族和其他IgAN家族的连锁和基因表达数据来鉴定负责高Gd-IgA 1水平的基因。此外，他建议对Gd-IgA 1进行第一次GWAS，以确定常见遗传变异对这种表型的可能贡献。他将通过在IgA 1产生细胞中的差异表达研究和对导致IgA 1异常糖基化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）的实验室进行，Terwilliger博士（共同导师）为他提供遗传分析方面的额外专业知识。考虑到该项目的跨学科性质，Krzysztof建立了一个由哥伦比亚大学不同部门和外部机构合作者组成的网络。Krzysztof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强大背景之上。他还将获得实验室方法的“实践”培训。从长远来看，Krzysztof希望建立一个高效的独立实验室，继续他在复杂疾病遗传学领域的科学研究。 公共卫生相关性：该项目旨在发现导致伊加肾病（全球最常见的原发性肾小球肾炎）的IgA 1分子异常的基因和途径。对导致产生异常IgA 1的遗传缺陷的拟议研究将为开发这种严重疾病的有效治疗方法奠定基础。

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.