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) 由 21 三体 (T21) 引起，具有许多相关缺陷，其标志是 100- 患先天性结肠无神经节病（HSCR 或先天性结肠无神经节病）的风险增加一倍。这个的机制关联是难以捉摸的，但一个关键线索是，一个常见的 RET 增强子变体与非综合征型 HSCR 也与有 HSCR 的 DS 病例相关，但与没有 HSCR 的 DS 病例无关。这些数据表明该关联是由于 21 号染色体 (HSA21) 基因剂量增加导致 RET-EDNRB 失调所致基因调控网络（GRN）增加 HSCR 风险，这一机制可能解释其他 DS 特征。一特定的 HSA21 候选者是 SOD1，一种假定的 RET 负调节因子，可以进一步减少 RET 具有 RET 缺陷增强子等位基因的 DS 病例中的表达。此外，非整倍体特异性蛋白质失衡还可以影响细胞增殖和HSCR。在这里，我们提出研究人类遗传学的三个目标，工程多能干细胞 (iPSC) 和 HSA21 基因和 RET 小鼠模型的功能基因组学，了解HSA21基因特异性和T21特异性遗传效应导致HSCR-的机制相关 DS。