Why do Down Syndrome patients have high risk of Hirschsprung disease?

为什么唐氏综合症患者患先天性巨结肠的风险很高？

基本信息

批准号：
10528177
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 248.66万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528177
关键词：
3&apos Untranslated Regions Affect Alleles Aneuploidy Binding Biochemical Biological Assay Blood specimen Cardiovascular system Cell Differentiation process Cell Line Cell Proliferation Cells Chromosome 21 Code Colonic Aganglionosis Complementary DNA Congenital Megacolon Data Defect Disease Disease susceptibility Down Syndrome Embryo Engineering Enhancers Enteral Enteric Nervous System Exons Family Gastrointestinal tract structure Gene Expression Gene Pool Genes Genetic Genetic Nondisjunction Genetic Screening Haplotypes Human Human Engineering Human Genetics Immune Immunofluorescence Immunologic In Situ Hybridization Individual Internal Ribosome Entry Site Joints Lead Link Meiosis Methods Molecular Analysis Mus Musculoskeletal Neural Crest Cell Neurologic Neurons Organ Parents Pathology Pathway interactions Patients Phenotype Play Pluripotent Stem Cells Population Proteins Proteome RET gene RNA Risk Role Site Statistical Data Interpretation Stress Syndrome System Testing Trisomy Validation Variant base chromosome loss disorder risk dosage functional genomics gain of function gene regulatory network genetic association genetic testing genetic variant high risk induced pluripotent stem cell mouse model neurogenesis novel overexpression proband single-cell RNA sequencing spatiotemporal stem cell differentiation stem cell model superoxide dismutase 1 trait transcriptome sequencing transmission process

项目摘要

ABSTRACT: Down syndrome (DS), resulting from trisomy 21 (T21), has many associated defects, a hallmark being the 100- fold higher risk of Hirschsprung disease (HSCR or congenital colonic aganglionosis). The mechanism of this association is elusive, but a critical clue is that a common RET enhancer variant, associated with non- syndromic HSCR, is also associated with DS cases with HSCR but not DS cases without. These data suggest that the association is from increased dosage of chromosome 21 (HSA21) genes dysregulating the RET-EDNRB gene regulatory network (GRN) to increase HSCR risk, a mechanism likely explaining other DS traits. One specific HSA21 candidate is SOD1, a putative negative regulator of RET, that can further reduce RET expression in DS cases with RET deficiency enhancer alleles. Further, aneuploidy-specific protein imbalance can also affect cell proliferation and HSCR. Here, we propose three aims investigating human genetics, functional genomics in engineered pluripotent stem cells (iPSC) and mouse models of HSA21 genes and RET, to understand the mechanisms by which HSA21 gene-specific and T21-specific genetic effects lead to HSCR- associated DS.

抽象的：唐氏综合症（DS）是由21（T21）产生的，具有许多相关的缺陷，标志是100- 折叠赫希斯普伦疾病（HSCR或先天性结肠Aganglioniso）的较高风险。这个机制关联是难以捉摸的，但一个关键的线索是，与非 - 综合征HSCR也与没有HSCR的DS病例相关，但没有DS病例。这些数据暗示该关联是来自增加染色体21（HSA21）基因的剂量增加的ret-Ednrb基因基因调节网络（GRN）增加了HSCR风险，这种机制可能解释了其他DS特征。一特定的HSA21候选者是SOD1，是RET的假定负调节器，可以进一步降低RET 在具有RET缺乏症增强子等位基因的DS病例中的表达。此外，非整倍性特异性蛋白质失衡也可能影响细胞增殖和HSCR。在这里，我们提出了调查人类遗传学的三个目标，工程多能干细胞（IPSC）的功能基因组学和HSA21基因的小鼠模型，RET，RET，了解HSA21基因特异性和T21特异性遗传效应的机制导致HSCR- 相关的DS。