Genomics of glomerular disease

肾小球疾病的基因组学

基本信息

批准号：
10203943
负责人：
KRZYSZTOF KIRYLUK
金额：
$ 87.01万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-14 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203943
关键词：
APOL1 gene Accounting Address African American Autoimmune Autoimmune Diseases Biological Biological Markers Biopsy Blood Clinical Collaborations Communities Coupled Data Data Set Diabetes Mellitus Diagnosis Disease Disease Pathway End stage renal failure Etiology Focal Segmental Glomerulosclerosis Gene Expression Profile Gene Expression Regulation Genetic Genetic Predisposition to Disease Genetic Risk Genetic Translation Genetic Variation Genetic study Genomic medicine Genomics Hypertension IGA Glomerulonephritis Immune Inflammatory Inflammatory Bowel Diseases Institutes International Investments Kidney Failure Knowledge Lupus Maps Mediating Membranous Glomerulonephritis Meta-Analysis Molecular Molecular Disease Molecular Profiling Mutation National Institute of Diabetes and Digestive and Kidney Diseases Nephrotic Syndrome Outcome Participant Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Population Prevention Prospective Studies Prospective cohort Regulator Genes Renal glomerular disease Resources Risk Role Sample Size Sampling South Asian Specificity Steroids Subcategory Susceptibility Gene System Therapeutic Translating United States Variant admixture mapping case control cell type clinical translation cohort design disorder subtype exome functional genomics gene function genetic approach genetic architecture genetic association genetic resource genetic variant genome sequencing genome wide association study genomic data genomic locus insertion/deletion mutation insight kidney biopsy new therapeutic target novel novel therapeutic intervention novel therapeutics peripheral blood rare variant risk variant screening therapeutic target transcriptome transcriptomics treatment response validation studies whole genome

项目摘要

Abstract: Glomerular disorders represent the third-most common cause of end-stage renal disease after diabetes and hypertension. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and minimal change disease (MCD) account for the majority of idiopathic glomerular diseases. Recent genetic studies have identified several genetic loci for these disorders and have begun to identify critical molecular pathways involved in their pathogenesis. However, well-designed and adequately powered genetic association studies are still missing for most glomerular disease types. Moreover, the field is faced with major challenges, including the need to validate the new loci across diverse patient cohorts, understand dysregulated pathways downstream of risk alleles and their consequences on clinical outcomes, define disease-specificity and interactions of risk alleles, and place their functional consequences within a coherent biological network. Such insights can then be translated into clinical benefits, including reliable biomarkers, effective strategies for screening and prevention, and rational selection of potential therapeutic targets. This proposal will address the above challenges by aiming to discover, validate, and fine-map known and novel genetic susceptibility loci by collaborative genetic studies. This will include a pioneering partnership with AstraZeneca and Columbia's Institute for Genomic Medicine to perform whole genome sequencing (WGS) of 4,000 cases of glomerular disease, including the entire CureGN study, the largest prospective cohort of patients with glomerular disorders. This will be followed by international meta-analyses and genetic validation studies in additional 26,000 cases of biopsy-confirmed primary glomerular disorders. Next, we will aim to discover precise pathogenic mechanisms underpinning each of the new genetic loci using systems genetics studies in the CureGN cohort. We will integrate the genetic data with blood transcriptomic studies and clinico-pathologic analyses to identify the key molecular disease drivers and their clinical and histopathologic consequences. Our studies will leverage the largest investment of NIDDK in glomerular diseases to refine the molecular pathogenesis and will be critical in defining targets for novel therapeutic interventions.

抽象的：肾小球疾病是继糖尿病和肾病之后导致终末期肾病的第三大常见原因。高血压。 IgA 肾病 (IgAN)、局灶节段性肾小球硬化症 (FSGS)、膜性肾病 (MN) 和微小病变 (MCD) 占特发性肾小球疾病的大多数。最近的遗传学研究已经确定了这些疾病的几个遗传位点，并已开始确定关键的参与其发病机制的分子途径。然而，精心设计且动力充足的遗传大多数肾小球疾病类型的关联研究仍然缺失。此外，该领域还面临着重大挑战，包括需要在不同患者群体中验证新基因座，了解失调风险等位基因的下游途径及其对临床结果的影响，定义疾病特异性和风险等位基因的相互作用，并将其功能后果置于连贯的生物网络中。这些见解可以转化为临床效益，包括可靠的生物标志物、有效的策略筛查和预防，合理选择潜在的治疗靶点。该提案将解决通过旨在发现、验证和精细绘制已知和新的遗传易感性位点来应对上述挑战合作遗传学研究。这将包括与阿斯利康和哥伦比亚的开创性合作伙伴关系基因组医学研究所将对 4,000 例肾小球病例进行全基因组测序 (WGS) 疾病，包括整个 CureGN 研究，这是最大的肾小球疾病患者前瞻性队列。随后将对另外 26,000 个病例进行国际荟萃分析和基因验证研究活检证实的原发性肾小球疾病。接下来，我们的目标是发现精确的致病机制使用 CureGN 队列中的系统遗传学研究来支持每个新的遗传位点。我们将将遗传数据与血液转录组研究和临床病理分析相结合，以确定关键分子疾病驱动因素及其临床和组织病理学后果。我们的研究将利用 NIDDK 在肾小球疾病方面最大的投资，旨在完善分子发病机制，这对于确定新的治疗干预措施的目标。