Integration of genomics and transcriptomics to investigate biological pathways in very early onset IBD

整合基因组学和转录组学研究极早发 IBD 的生物学途径

基本信息

批准号：
10617296
负责人：
Judith Rachel Kelsen
金额：
$ 67.74万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617296
关键词：
6 year old Age Alleles Allelic Imbalance Alternative Splicing Biological Biological Assay Biological Process Candidate Disease Gene Cells Child Child Care Colon Complex Data Data Set Defect Detection Development Diagnosis Disease Event Family Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genomics Goals Heterogeneity Immune Incidence Individual Inflammatory Bowel Diseases Knowledge Link Mendelian disorder Methods Modification Molecular Morbidity - disease rate Mutation Parents Pathogenesis Pathway interactions Patient Recruitments Patients Peripheral Blood Mononuclear Cell Phenotype Recording of previous events Refractory Refractory Disease Role Single-Gene Defect Source Spliced Genes Testing Tissues Transcript Translating Variant candidate identification candidate validation causal variant cell type cohort conventional therapy differential expression disease diagnosis disease phenotype early onset exome sequencing genetic analysis genetic risk factor genetic variant genome sequencing genome wide association study improved individualized medicine infancy innovation insight novel novel therapeutic intervention patient subsets risk variant single cell analysis single-cell RNA sequencing targeted treatment transcriptome transcriptome sequencing transcriptomics whole genome

项目摘要

ABSTRACT The genomic contribution to the development of very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at <6 years of age, remains understudied, yet elucidation of genetic risk factors would undoubtedly enhance our understanding of pathogenesis and suggest novel therapeutic approaches. The aggressive phenotype, often refractory to conventional therapy, early onset, and strong family history points to an enrichment of monogenic defects. Indeed, we and others have identified causal variants in VEO-IBD that has changed care for these children. Whole exome sequencing has radically changed our approach to VEO-IBD, however, it has only been successful in ~18% of cases, despite evidence highly suggestive of an underlying genetic defect. In addition, linking the identified variant to the development of the VEO-IBD phenotype remains difficult. The goal of this proposal is to widen our genetic analysis through whole genome sequencing (WGS) and leverage transcriptome modifications to enhance our capacity in identifying causal variants. Our central hypothesis is that a proportion of VEO-IBD is a monogenic disease, a subset of which will alter gene transcription, and transcriptome analysis, including single cell analysis, will allow us to more rapidly and accurately identify such mutations among the detected candidate variants. Using a novel innovative method, based on WGS, we will expand our repertoire of causal defects in VEO-IBD. We will integrate these findings with RNA-seq and scRNA-seq data, which can generate a more sensitive and specific approach to detect causal variants and characterize their mechanism of action. In addition, when WGS cannot identify a clear causal variant, RNA-seq and scRNA-seq can provide insight into the underlying disease mechanism, supporting the implication of candidate mutations. To test our central hypothesis, in Specific Aim 1 we will expand our dataset of potential causal mutations in VEO- IBD through WGS. We will validate candidate genes in additional VEO-IBD cases. In Specific Aim 2, we will test the ability of transcriptional profiling of colonic tissue and PBMCs to enhance the identification of novel causal variants of VEO-IBD. Finally, in Specific Aim 3, using scRNA sequencing, we will assess the colonic and immune cell heterogeneity and characterize genes and pathways associated with infantile onset IBD using transcriptional profiling of individual cells from colonic tissue and PBMCs. Completion of this project will result in the identification of novel genetic causes of VEO-IBD, providing a fertile source of biologic processes to pursue to better understand the basic mechanisms of disease, with the ultimate goal of translating this knowledge into improved care for children with VEO-IBD through individualized and targeted therapy.

抽象的基因组对非常早期发作炎症性肠病（VEO-IBD）的发展的贡献，IBD 诊断在<6岁时，仍在研究，但阐明遗传危险因素无疑会增强我们对发病机理的理解，并提出新颖的治疗方法。侵略性表型，通常对常规疗法，早期发作和强大的家族史表明富集单基因缺陷。实际上，我们和其他人已经确定了veo-ibd中的因果变异，这改变了护理对于这些孩子。整个外显子组测序从根本上改变了我们对veo-ibd的方法，但是它具有尽管有证据表明潜在的遗传缺陷，但仅在约18％的病例中才成功。在此外，将确定的变体与VEO-IBD表型的发展联系起来仍然很困难。该建议的目的是通过整个基因组测序（WGS）和利用转录组修改以增强我们在识别因果变异的能力。我们的中心假设是，一定比例的veo-ibd是一种单基因疾病，其中一部分将改变基因转录，以及包括单细胞分析在内的转录组分析，将使我们能够更迅速，准确地识别检测到的候选变体之间的这种突变。使用一种基于WGS的新型创新方法，我们将扩大我们在VEO-IBD中的因果缺陷的曲目。我们将将这些发现与RNA-seq和 SCRNA-seq数据，可以生成一种更灵敏，更具体的方法来检测因果变体和表征他们的作用机理。另外，当WGS无法识别明确的因果变体时，RNA-seq Scrna-Seq可以提供对潜在疾病机制的见识，支持候选突变。为了检验我们的中心假设，在特定目的1中，我们将扩展我们的数据集的潜在因果突变的数据集 IBD通过WGS。我们将在其他VEO-IBD病例中验证候选基因。在特定目标2中，我们将测试结肠组织和PBMC的转录分析能够增强新因果的鉴定的能力 veo-ibd的变体。最后，在使用SCRNA测序的特定目标3中，我们将评估结肠和免疫细胞异质性并表征与婴儿发作IBD相关的基因和途径从结肠组织和PBMC进行单个细胞的分析。该项目的完成将导致鉴定出新的遗传原因，从而提供肥沃追求生物学过程的来源，以更好地了解疾病的基本机制，最终通过个体化和靶向疗法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ruxolitinib: Targeted Approach for Treatment of Autoinflammatory Very Early Onset Inflammatory Bowel Disease.

DOI：
10.1016/j.cgh.2021.07.040
发表时间：
2022-06
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
0
作者：
Rudra S;Shaul E;Conrad M;Patel T;Moore A;Dawany N;Canavan MC;Sullivan KE;Behrens E;Kelsen JR
通讯作者：
Kelsen JR

A Pattern-based Pathology Approach to Very Early-onset Inflammatory Bowel Disease: Thinking Beyond Crohn Disease and Ulcerative Colitis.