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Mechanisms for cell signaling in the control of cardiomyogenesis

控制心肌发生的细胞信号传导机制

基本信息

批准号：
10522627
负责人：
Kunhua Song
金额：
$ 124.98万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522627
关键词：
Address Affect Age Alleles Animals Automobile Driving Cardiac Cardiac Myocytes Cardiac development Cells Child Chromosome 21 Congenital Abnormality Congenital Heart Defects Data Defect Development Down Syndrome Embryo Embryonic Heart GATA4 gene General Population Genes Genetic Genetic Diseases Healthcare Heart Abnormalities Heart Diseases Human Human Chromosomes IFNAR1 gene IFNAR2 gene IL10RB gene Impairment In Vitro Individual Interferon Receptor Interferons Janus kinase Knock-out Molecular Mus Newborn Infant Operative Surgical Procedures Pathway interactions Persons Pharmacology Population Predisposition Prevalence Regulation Research Risk Risk Factors Role Signal Pathway Signal Transduction Survival Rate Transcript Trisomy United States Ursidae Family WNT Signaling Pathway beta catenin cardiogenesis cell type congenital heart disorder dosage genome-wide heart function improved in vivo in vivo Model induced pluripotent stem cell inhibitor insight macrophage mortality mouse model novel novel diagnostics novel therapeutic intervention overexpression response restoration stem cell model

项目摘要

Project Summary/Abstract Down syndrome (DS), the condition caused by trisomy of human chromosome 21, affects approximately 1 in 700 newborns in the United States. Congenital heart defects (CHDs) are very frequent in children with DS with a prevalence of 50% compared to a risk of < 1% in typical children. Although remarkable advances in health care and cardiac correction surgery have improved the survival rate of children born with DS, CHDs are still a primary and significant risk factor for mortality in people with DS through age twenty. Using a combination of the human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16), a mouse model for DS, we identified increased dosage of interferon (IFN) receptor encoded by genes, IFNAR1, IFNAR2, IFNG2, and IL10RB on chromosome 21 (chr21) as a causative factor of CHDs in DS. The canonical Wnt signaling pathway was down-regulated during DS cardiogenesis in vitro and in vivo. Normalization of IFN signaling restored the canonical Wnt pathway and ameliorated cardiogenesis in DS. In this project, we propose to (1) determine molecular mechanisms by which increased IFN signaling down-regulates the Wnt/β-Catenin pathway during heart development in DS and (2) examine cell populations associated with response to increased IFN signaling during heart development in DS. The results from this project have the potential to facilitate the development of novel therapeutic strategies to benefiting both people with DS and typical children born with CHDs.

项目总结/摘要唐氏综合征（DS）是由人类21号染色体三体引起的疾病，在美国有700个新生儿。先天性心脏缺陷（CHD）在患有DS的儿童中非常常见，患病率为50%，而典型儿童的患病风险< 1%。尽管在健康方面的显著进步护理和心脏矫正手术提高了出生时患有DS的儿童的存活率，CHD仍然是一个在20岁之前DS患者死亡率的主要和重要危险因素。使用基于人诱导多能干细胞（iPSC）模型和Dp（16）1 Yey/+（Dp 16），DS的小鼠模型，我们确定了由基因IFNAR 1、IFNAR 2、IFNG 2和IFNAR 3编码的干扰素（IFN）受体的剂量增加， 21号染色体（chr 21）上的IL 10 RB作为DS中CHD的致病因子。经典Wnt信号转导通路在体外和体内DS心脏发生过程中下调。IFN信号的正常化恢复了经典Wnt通路和改善DS中的心脏发生。在本项目中，我们建议（1）确定 IFN信号转导增加下调Wnt/β-连环蛋白通路的分子机制 DS中的心脏发育和（2）检查与对增加的IFN信号传导的应答相关的细胞群在DS的心脏发育过程中。该项目的成果有可能促进新的治疗策略，使DS患者和典型的先天性CHD儿童受益。