Quantitative Genetics of Defective IgA1 Glycosylation in IgA Nephropathy

描述(由申请人提供)：Krzysztof Kiryluk，哥伦比亚大学助理教授，临床肾病专家，曾接受过生物统计学方面的正式培训。他的长期目标是发展一个独立的职业生涯，在IgA肾病和其他形式的肾脏疾病的遗传学方面进行翻译研究。这项建议的目的是培养他的科学发展、实验室技能，并建立他在统计遗传学方面的专业知识。IgA肾病是世界范围内引起原发性肾小球肾炎的最常见原因。大多数IgAN患者表现出典型的IgA1分子糖基化不足。血清半乳糖缺乏性IgA1(Gd-IgA1)水平升高是IgAN的一个有用的生物标志物。Gd-IgA1促进含Gd-Ig A1免疫复合体的形成和系膜沉积，但目前尚不清楚Ig AN患者高Gd-Ig A1的原因。近年来，建立了一种可靠的基于凝集素的检测高水平血清Gd-IgA1的酶联免疫吸附试验。Krzysztof利用这一检测方法证明，与无血缘关系的对照组相比，很大比例的IgAN患者及其家人的Gd-IgA1水平升高。此外，Krzysztof在一个家族性IgAN家系中进行了Gd-IgA1的全基因组连锁扫描，并在染色体10p14-15(LOD=4.4)上发现了一个主要易感基因。基于这些结果，他假设Gd-IgA1水平在一定程度上是由基因决定的。他建议通过整合来自这个和其他IgAN家系的连锁和基因表达数据来识别导致Gd-Ig A1水平高的基因(S)。此外，他建议对Gd-IgA1进行第一次GWA，以确定常见遗传变异对这种表型的可能贡献。他将通过对产生免疫球蛋白A1的细胞的差异表达研究和导致免疫球蛋白A1异常糖基化的基因的体外功能研究(S)来遵循他的发现。拟议的研究将在Gharavi博士(主要导师)的实验室进行，特威利格博士(共同导师)将为他提供基因分析方面的额外专业知识。考虑到这个项目的跨学科性质，Krzysztof建立了一个由哥伦比亚大学不同系和外部机构的合作者组成的网络。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。他还将接受实验室方法方面的“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IgA肾病的IgA1分子异常的基因和途径，IgA肾病是世界上最常见的原发性肾小球肾炎。对导致IgA1产生异常的遗传缺陷的研究将为开发有效的治疗这一严重疾病的方法奠定基础。

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.