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: 10545745
• 负责人: Sophie Astrof
• 金额: $ 46.83万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545745
• 关键词: 22q11; 3-Dimensional; Alleles; Applications Grants; Arteries; Blood; Blood Vessels; Branchial arch structure; Breathing; Candidate Disease Gene; Cardiovascular system; Cells; Chemotactic Factors; Chromosome abnormality; Circulation; Compensation; Congenital Abnormality; Coupled; DNA Sequence Alteration; Data; Defect; Development; DiGeorge Syndrome; Diagnosis; Eating; Embryo; Endothelial Cells; Endothelium; Ensure; Etiology; Fibroblast Growth Factor; Fibronectins; 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; Pathway interactions; Patients; Process; Quality of life; Route; Signal Transduction; Source; Stromal Cell-Derived Factor 1; Syndrome; Testing; Trees; Vascular Endothelial Growth Factors; Veins; Venous; Work; aortic arch; 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.

主动脉弓动脉及其分支是输送含氧血液的血管 从心脏到体循环主动脉弓动脉发育的缺陷导致致命的形式 先天性心脏病（CHD）由于体循环中断，例如，中断 主动脉弓B型（IAA-B）。这些缺陷通常与22 q11缺失综合征一起发生， 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CHD病因学提供有价值的见解 和潜在的治疗方法。主动脉弓动脉及其分支是在对称的 咽弓动脉（PAA）进入不对称血管树。我们证明了PAA内皮细胞 主要来源于第二心脏区域（SHF）的祖细胞。此外，我们发现基因突变 导致SHF衍生的内皮细胞缺陷引起IAA-B。这份申请书描述了两个 新的小鼠模型中，一个意想不到的来源的内皮祖细胞修复缺陷的SHF- 衍生的内皮细胞（EC）和挽救主动脉弓动脉形成。我们发现了一种替代品 修复PAA缺陷的内皮源已经开启了确定调节这种缺陷的机制的可能性。 补偿修复过程。我们还发现，代偿性内皮细胞并没有被募集， 22 q11缺失综合征的Tbx 1 +/-小鼠模型，导致IAA-B和新生儿致死率约为Tbx 1 +/-的65% 小鼠在这项拨款申请中，我们建议确定补偿EC的来源，调节机制， 补充内皮细胞的募集，以及Tbx 1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.验证代偿性内皮细胞来源于 2.确定调节代偿性EC募集以拯救弓的信号 动脉形成在这个建议中，我们将使用新的小鼠品系，基因工程，定量3D共聚焦显微镜， 成像、原位杂交和RNAseq来揭示调节代偿反应的候选基因。 在完成拟议的工作后，我们将揭示补偿和鲁棒性的内在机制， 通过替代机制确保新生儿的生存能力。利用这些机制将 为未来冠心病的治疗提供了新的机会。