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.

项目摘要/摘要唐氏综合症（DS）是由人类染色体的三体造成的状况，影响约1 美国有700名新生儿。先天性心脏缺陷（CHD）经常在患有DS的儿童中典型儿童的风险<1％，患病率为50％。虽然在健康方面取得了显着进步护理和心脏矫正手术提高了患有DS的儿童的存活率，CHD仍然是 DS至20岁的人死亡的主要和重要危险因素。结合人类诱导的多能干细胞（IPSC）基于DP（16）1yey/+（DP16），DS的小鼠模型，我们鉴定出通过基因，IFNAR1，IFNAR2，IFNG2和 IL10RB在染色体21（CHR21）上是Ds中CHD的病因。规范的Wnt信号通路在体外和体内DS心脏病发生过程中被下调。 IFN信号的归一化恢复了 DS中的规范WNT途径和改善心脏病。在这个项目中，我们建议（1）确定分子机制增加了IFN信号传导下调Wnt/β-catenin途径。 DS的心脏发育和（2）检查与IFN信号增加的反应有关的细胞群在DS心脏发展期间。该项目的结果有可能促进新颖的治疗策略，使DS和典型儿童出生的CHD患者受益。