Evaluation of Hedgehog signaling-dependent heart development in a mouse model of Down Syndrome

唐氏综合症小鼠模型中刺猬信号依赖性心脏发育的评估

• 批准号: 10747227
• 负责人: Ivan Paul Moskowitz
• 金额: $ 44.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-26 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10747227
• 关键词: Address; Area; Award; Basic Science; Cardiac; Cardiopulmonary; Cell Differentiation process; Chromosome 21; Chromosomes; Cilia; Congenital Abnormality; Defect; Development; Down Syndrome; Erinaceidae; Etiology; Evaluation; Exhibits; Failure; Funding; Gene Expression; Genes; Genomics; Heart; Heart Abnormalities; Human; Human Chromosomes; Hybrids; Laboratories; Link; Methods; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutant Strains Mice; Organ; Organogenesis; Parents; Pathology; Population; Risk; Signal Transduction; Signaling Protein; Structural defect; Testing; Translating; Work; atrioventricular septal defect; cardiogenesis; congenital heart disorder; gene regulatory network; high reward; high risk; mortality; mouse model; progenitor; segregation; single cell sequencing; smoothened signaling pathway; transcription factor

The fundamental question for the field of Down Syndrome (DS) basic research is how an extra copy of human chromosome 21 (HSA21) translates into the organ-specific pathologies that are observed in the DS population. Structural pathologies in DS include congenital heart malformations, including a 2000-fold increased risk for Atrioventricular Septal Defects (AVSDs). A mechanistic understanding of DS-specific organogenesis defects is lacking, and specifically, how Trisomy 21 (T21) causes Congenital Heart Disease is poorly understood. In the parent award, we have defined Hedgehog (Hh) signaling as an explicit development timer of cardiac differentiation during mammalian development. Furthermore, there is plentiful evidence that suggests that T21 causes Hedgehog signaling defects. In this supplement, we propose to evaluate cardiac progenitors in Tc(HSA21q;MAC)1Yakaz ("TcMAC21"), a new mouse model of DS with a stably segregating HSA21q-MAC hybrid chromosome that is nearly complete compared to the human HSA21q chromosome. Importantly, TcMAC21 mice exhibit penetrant AVSDs. We propose to determine whether AVSDs in TcMAC21 result from failure of Hedgehog-signaling dependent timing control of SHF cardiac progenitor differentiation timing. This Supplement addresses INCLUDE Component 1: Targeted high risk - high reward basic science studies in areas highly relevant to Down syndrome. We propose the transformative hypothesis that the cause of cardiac defects in DS is failure of Hedgehog-signaling-dependent timing control of progenitor differentiation, resulting in precocious differentiation, reduction of cardiac progenitor numbers, and cardiac morphogenesis failure resulting in CHD.

唐氏综合症（DS）基础研究领域的根本问题是如何在一个额外的 人类21号染色体（HSA 21）的拷贝转化为器官特异性病理， 在DS人群中观察到。DS的结构性病理包括先天性心脏病 畸形，包括房室间隔缺损（AVSD）的风险增加2000倍。 缺乏对DS特异性器官发生缺陷的机制理解，具体来说， 21三体（T21）如何导致先天性心脏病还知之甚少。在母 我们将Hedgehog（Hh）信号定义为心脏发育的明确计时器， 哺乳动物发育过程中的分化。此外，有大量证据表明， 表明T21导致Hedgehog信号缺陷。在本补充文件中，我们建议 评估Tc（HSA 21 q;MAC）1 Yakaz（“TcMAC 21”）中的心脏祖细胞， DS具有稳定分离的HSA 21 q-MAC杂交染色体，与 人类HSA 21 q染色体。重要的是，TcMAC 21小鼠表现出渗透AVSD。我们 建议确定TcMAC 21中的AVSD是否由Hedgehog信号传导的失败引起 SHF心脏祖细胞分化定时的依赖性定时控制。这种补充剂 组成部分1：有针对性的高风险-高回报基础科学研究， 与唐氏综合症高度相关的领域。我们提出了一个变革性的假设， DS中心脏缺陷的原因是Hedgehog信号依赖的时序控制失败， 祖细胞分化，导致早熟分化，心脏祖细胞减少 数量，以及导致CHD的心脏形态发生衰竭。