Identification of compensatory mechanisms to rescue aortic arch artery defects

确定挽救主动脉弓动脉缺损的代偿机制

• 批准号: 10389147
• 负责人: Sophie Astrof
• 金额: $ 46.83万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389147
• 关键词: 22q11; 3-Dimensional; Alleles; Applications Grants; Arteries; Blood; Blood Circulation; Blood Vessels; Branchial arch structure; Breathing; Candidate Disease Gene; Cardiovascular system; Cells; Chemotactic Factors; Chromosome abnormality; Congenital Abnormality; Coupled; DNA Sequence Alteration; Data; Defect; Development; DiGeorge Syndrome; Diagnosis; Eating; Embryo; Endothelial Cells; Endothelium; Ensure; Etiology; Fibroblast Growth Factor; Fibronectins; Financial compensation; Fluorescent in Situ Hybridization; Future; Genes; Genetic Engineering; Goals; Growth Factor; Heart; Human; Hypoplastic Left Heart Syndrome; Hypoxia; Immunohistochemistry; Impairment; In Situ Hybridization; Integrins; Interruption; KDR gene; Knock-in Mouse; Knowledge; Lead; Maps; Mediating; Modeling; Morphogenesis; Mouse Strains; Mus; Mutagenesis; Mutate; Neonatal; Newborn Infant; Pathogenicity; Patients; Process; Quality of life; Route; Signal Pathway; Signal Transduction; Source; Syndrome; Testing; Trees; Vascular Endothelial Growth Factors; Veins; Venous; Work; aortic arch; base; confocal imaging; congenital heart disorder; dosage; endothelial stem cell; follow-up; insight; mouse development; mouse model; mutant; mutant mouse model; novel; prevent; progenitor; prophylactic; recruit; repaired; response; transcription factor; transcriptome sequencing

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.

项目摘要主动脉弓动脉及其分支是血管，可伸出含氧血液 从心脏到全身循环。主动脉弓动脉发育的缺陷导致致命形式 由于全身循环中的中断引起的先天性心脏病（CHD），例如中断 主动脉弓类B（IAA-B）。这些缺陷通常与22q11缺失综合征结合在一起，最多 人类常见的先天性染色体异常综合症。因此，了解基因和 调节主动脉弓动脉发展的机制将提供对冠心病学的有价值的见解 和潜在的治疗。对称的重塑后，主动脉弓动脉及其分支形式 咽弓动脉（PAAS）进入不对称的血管树。我们证明了PAA内皮 主要来自第二心脏场（SHF）中的祖细胞。此外，我们发现基因突变 导致SHF衍生的内皮导致IAA-B的缺乏。该赠款申请描述了两个 新的小鼠模型，其中内皮祖细胞的意外来源可以修复SHF-的缺陷 衍生的内皮细胞（ECS）并营救主动脉弓形成。我们发现替代方案 维修PAA缺陷的内皮来源开放了确定调节此机制的机制 补偿维修过程。我们还发现，补偿性内皮没有在 22q11缺失综合征的TBX1 +/-小鼠模型，导致IAA-B和新生儿致死性，〜65％的TBX1 +/- 老鼠。在此赠款申请中，我们建议确定补偿EC的来源，调节机制 补偿性内皮的募集以及TBX1如何调节这一过程。为了实现这些目标， 我们提出以下具体目的：1测试补偿内皮的假设 从静脉和2个确定调节补偿性EC招募以营救拱门的信号 动脉形成。在此提案中，我们将使用新颖的小鼠菌株，基因工程，定量3D共焦 成像，原位杂交和RNASEQ，以发现调节补偿性反应的候选基因。 完成拟议的工作后，我们将发现薪酬和鲁棒性的先天机制， 因此，通过替代机制确保了新生儿的生存能力。利用这些机制 为将来提供新的冠心病治疗机会。