Identification of compensatory mechanisms to rescue aortic arch artery defects

项目摘要：主动脉弓动脉及其分支是输送含氧血液的血管。 从心脏到全身循环。主动脉弓动脉发育缺陷导致致命性畸形 由于体循环中断而导致的先天性心脏病(先天性心脏病)(S)，例如 B型主动脉弓(IAA-B型)。这些缺陷经常与22q11缺失综合征一起发生，最常见的是 人类常见的先天性染色体异常综合征。因此，了解基因和 调节主动脉弓动脉发育的机制将为冠心病病因学提供有价值的见解 以及潜在的治疗方法。主动脉弓动脉及其分支是在对称性动脉重建后形成的 咽弓动脉(PaaS)进入不对称血管树。我们证明了PAA内皮细胞 主要来源于第二心区(SHF)的祖细胞。此外，我们发现基因突变 导致SHF来源的内皮细胞的缺陷导致IAA-B。这份赠款申请描述了两个 一种新的小鼠模型，在该模型中，一种意想不到的内皮祖细胞来源修复了SHF-1的缺陷 衍生内皮细胞(ECs)，挽救主动脉弓动脉的形成。我们发现了另一种选择 修复PAA缺陷的内皮来源为确定调节机制打开了可能性 补偿性修复过程。我们还发现，代偿性内皮细胞不被招募。 22q11缺失综合征的TBX1+/-小鼠模型，导致~65%的TBX1+/-的IAA-B和新生儿死亡率 老鼠。在这项赠款申请中，我们建议确定补偿ECS的来源、监管机制 代偿性内皮细胞的募集，以及TBX1如何调节这一过程。为了实现这些目标， 我们提出了以下具体目标：1检验代偿性内皮细胞起源于 从静脉，以及2，以确定信号，调节招募的代偿内皮细胞，以拯救ARCH 动脉形成。在这项提议中，我们将使用新的小鼠品系，基因工程，定量3D共聚焦 成像、原位杂交和RNAseq以发现调节代偿反应的候选基因。 在完成拟议的工作后，我们将揭示固有的补偿和健壮性机制， 从而通过替代机制确保新生儿的生存能力。利用这些机制将 为今后冠心病的治疗提供新的契机。

PROJECT SUMMARY The aortic arch artery and its branches are blood vessels that route the oxygenated blood from the heart to the systemic circulation. Defects in the development of the aortic arch artery lead to lethal forms of congenital heart disease (CHD) due to interruption(s) in the systemic circulation, for example, the interrupted aortic arch type B (IAA-B). These defects often occur in conjunction with 22q11 deletion syndrome, the most common congenital chromosomal abnormality syndrome in humans. Therefore, understanding genes and mechanisms regulating the development of the aortic arch artery will provide valuable insights into CHD etiology and potential treatments. Aortic arch artery and its branches form following the remodeling of the symmetrical pharyngeal arch arteries (PAAs) into the asymmetrical vascular tree. We demonstrated that the PAA endothelium is mainly derived from progenitors in the second heart field (SHF). Furthermore, we found that genetic mutations resulting in the deficiency in the SHF-derived endothelium cause IAA-B. This grant application describes two new mouse models in which an unexpected source of endothelial progenitors repairs the deficiency in the SHF- derived endothelial cells (ECs) and rescues aortic arch artery formation. Our discovery of an alternative endothelial source that repairs PAA defects has opened the possibility to determine mechanisms regulating this compensatory repair process. We also discovered that the compensatory endothelium is not recruited in the Tbx1+/- mouse model of 22q11 deletion syndrome, resulting in IAA-B and neonatal lethality in ~65% of Tbx1+/- mice. In this grant application, we propose to determine the source of compensating ECs, mechanisms regulating the recruitment of compensatory endothelium, and how Tbx1 regulates this process. To accomplish these goals, we propose the following Specific Aims: 1 To test the hypothesis that the compensating endothelium is derived from a vein, and 2 To determine signals regulating the recruitment of the compensatory ECs to rescue arch artery formation. In this proposal, we will use novel mouse strains, genetic engineering, quantitative 3D confocal imaging, in situ hybridization, and RNAseq to uncover candidate genes regulating the compensatory response. Upon completing the proposed work, we will uncover innate mechanisms of compensation and robustness, whereby a newborn's viability is ensured through alternative mechanisms. Harnessing these mechanisms would provide new opportunities for treatments of CHD in the future.