Rare variant analysis of glomerulonephritis

项目摘要 伊加肾病（IgAN）是世界范围内最常见的原发性肾小球肾炎。Igan是一个进步的 以肾小球滤过率（GFR）逐渐下降为特征的疾病，导致终末期 15%-20%的患者在疾病发作后10年内患有肾病（ESRD）。在我们的研究中， IgAN的发病机制是血清和肾小球中Gd-IgA 1水平升高， 免疫沉积，尽管潜在的分子机制仍不清楚。五年K 01 申请提出了一个研究和培训计划，将支持申请人的道路上， 成为NIH资助的独立研究者，专注于研究患者的罕见致病变种 根据Gd-IgA 1水平，IgAN和单细胞转录景观作为新兴指标 IgAN的生物标志物。培训计划建立在候选人以前的培训和经验的基础上， 利用导师团队和研究环境，促进候选人的发展 专业知识（1）临床领域知识，以解释改变的生物学和临床影响（2） 人类遗传学问题的统计和计算方法的发展（3） 用于与肾小球肾炎相关的人免疫细胞的分子表型的单细胞测序和（4） 在人类受试者的科学研究中采取负责任和合乎道德的行为。该研究项目将进行 基于已知的孟德尔遗传算法，对2，500例IgAN患者的外显子组测序数据进行诊断注释 肾脏疾病的原因（目标#1），发现新的基因与IgAN使用崩溃的方法， 罕见变体（2，500个IgAN外显子组数据和> 6，000个对照外显子组）（目标#2），并鉴定细胞身份和 Gd-IgA 1水平高或低的IgAN患者中伊加产生细胞的转录异质性， 使用单细胞RNA-seq的对照（目标#3）。成功完成这项研究将提高我们的 了解IgAN中罕见致病性变异的作用，并促进临床诊断和个性化 疾病风险分析。这些数据沿着通过K 01奖开发的研究专业知识将导致 到一个成功的R 01级的建议，其目标是描绘肾小球肾炎的发病机制。的 这一系列研究的最终目标是开发自身免疫介导的肾脏疾病的遗传决定因素， 疾病可能导致生物标志物的识别，用于早期检测，干预和开发新的治疗方法。 NIDDK遗传学和生物因子战略研究计划（NIDDK Strategic Research Plans for Genetics and Biological Factors）

PROJECT SUMMARY IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN is a progressive disease characterized by a gradually decreasing glomerular filtration rate (GFR), which results in end-stage renal disease (ESRD) in 15% to 20% of patients within 10 years of disease onset. A key observation in our understanding of the pathogenesis of IgAN is the elevated level of Gd-IgA1 in both serum and glomerular immune deposits, although the underlying molecular mechanisms are still unclear. This five-year K01 application presents a program for research and training that will support the applicant on a path towards becoming an NIH-funded independent investigator, focused on studying rare pathogenic variants in patients with IgAN and single-cell transcriptional landscape according to the level of Gd-IgA1 as an emerging indicator of biomarker of IgAN. The training plan builds on the candidate's previous training and experience, and capitalizes on a mentorship team and a research environment to foster development of the candidate's expertise in (1) clinical domain knowledge to interpret the biological and clinical impact of alterations (2) development of statistical and computational methods for problems in human genetics (3) applications of single-cell sequencing for molecular phenotyping of human immune cells relevant to glomerulonephritis and (4) responsible and ethical conduct in scientific research in human subjects. The research project will conduct diagnostic annotation of exome sequencing data in 2,500 patients with IgAN based on known Mendelian causes of kidney disease (Aim #1), discover novel genes associated with IgAN using collapsing methods for rare variants (2,500 IgAN exome data and > 6,000 control exomes) (Aim #2) and identify cell identity and transcriptional heterogeneity of IgA producing cells in IgAN patients with high or low Gd-IgA1 compared to controls using single-cell RNA-seq (Aim #3). Successful completion of this study will improve our understanding of the role of rare pathogenic variants in IgAN and facilitate clinical diagnosis and personalized disease-risk profiling. These data along with the research expertise developed through this K01 award will lead to a successful R01-level proposal with the goal of delineating pathogenesis of glomerulonephritis. The ultimate goal of this line of research is to develop genetic determinants of autoimmune-mediated renal diseases may lead to identification of biomarkers for early detection, intervention and development of novel treatments (NIDDK Strategic Research Plans for Genetics and Biological Factors).