Exploring the Role of the anterior SHF in AVSD Pathogenesis

探索前 SHF 在 AVSD 发病机制中的作用

基本信息

批准号：
10854097
负责人：
Arno Wessels
金额：
$ 24.55万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10854097
关键词：
Administrative Supplement Animal Model Anterior Atrial Heart Septal Defects Candidate Disease Gene Cardiac Cause of Death Cells Chromosome 16 Chromosome 21 Complex Congenital Abnormality Congenital Heart Defects Defect Development Diagnosis Dorsal Down Syndrome Down-Regulation Embryo Endocardium Engineering Event Funding General Population Genes Genetic Health Heart Heart Abnormalities Heart Atrium Human Chromosomes Individual Investigation Life Longevity Mesenchymal Modeling Modification Molecular Morphology Mus National Heart, Lung, and Blood Institute Pathogenesis Patients Phenotype Play Publishing Research Role Specimen Structural defect Structure Testing Ventricular Ventricular Septal Defects atrioventricular septal defect cardiogenesis congenital heart disorder experimental study insight interest migration mouse Trisomy 16 mouse model offspring prevent response single-cell RNA sequencing theories virtual

项目摘要

This application for an Administrative Supplement to our active R01-HL122906 is being submitted in response to PA-20-272 in accordance with NOT-OD-22-137 (“Availability of Administrative Supplements for the INCLUDE - INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome - Project”). Significance of application in relation to Down syndrome (DS): Atrioventricular septal defects (AVSDs) are complex congenital heart defects but relatively rare in the general population. Approximately 0.05% of babies born have an AVSD. They are, however, very common in DS patients (35-40% of DS babies are diagnosed with an AVSD). In this project we will address one of the priorities of the National Heart, Lung, and Blood Institute (NHLBI) as we will, using animal models, focus on the morphological events involved in the pathogenesis of AVSDs which, if untreated, can be the cause of death during the first year of life. Abstract: The study of heart development as it relates to congenital heart disease has been the focus of the Wessels lab for years. This proposal is a logical extension of studies that were initiated after the discovery of the Dorsal Mesenchymal Protrusion (DMP) by the PI. We identified the DMP as a structure critically important for the development of the atrioventricular (AV) mesenchymal complex and determined that the DMP was derived from the Second Heart Field (SHF). We developed the hypothesis that the DMP could be involved in the pathogenesis of AVSDs. Indeed, in our study of the Trisomy 16 (Ts16) mouse, a model for DS, we found that AVSDs were associated with hypoplasia of the DMP. Furthermore, we demonstrated that experimentally deleting candidate genes believed to be essential for proper SHF development (Alk3 and Smo) resulted in perturbation of DMP formation and AVSD pathogenesis. Analysis of the SHF;Smo mouse revealed downregulation of several genes including Sox9. Based on our earlier studies, we predicted that Sox9 would play a critical role in DMP development and AV septation. Surprisingly, while SHF-specific Sox9 deletion resulted in AVSD in 50% of SHF;Sox9 offspring, it was not the result of DMP hypoplasia, but rather associated with failed development of the mesenchymal cap. Importantly, virtually all specimens inspected had developed a ventricular septal defect (VSD). This (published) observation in combination with results of our studies on AVSD pathogenesis (see: Research Plan) have led to new theories about the role of the anterior and posterior SHF (aSHF and pSHF) in the pathogenesis of the atrial and ventricular defects in the context of DS. We propose experiments with different mouse models, including the TcMAC21 model for DS, to test these hypotheses. In addition, we will initiate single cell RNAseq experiments to gain insight into the molecular mechanisms involved in the pathogenesis of AVSDs, specifically focusing on the role of the embryonic outflow tract in VSD pathogenesis.

该申请向我们的活动R01-HL122906提交给我们的Active R01-HL122906的申请根据NOT-OD-22-137对PA-20-272的回应包括 - 研究整个生命周期的同时发生条件以了解唐氏综合症 - 项目”）。与唐氏综合症有关的施用意义（DS）：房屋间隔缺陷（AVSD）为复杂的先天性心脏缺陷，但在普通人群中相对较少。大约0.05％的婴儿天生有一个AVSD。但是，它们在DS患者中非常普遍（35-40％的DS婴儿被诊断出患有 AVSD）。在这个项目中，我们将解决国家心脏，肺和血液的优先事项之一研究所（NHLBI）正如我们将使用动物模型的那样，专注于涉及的形态事件 AVSD的发病机理，如果未经治疗，可能是生命第一年的死亡原因。摘要：与先天性心脏病有关的心脏发育的研究一直是 Wessels实验室多年。该提议是在发现后启动的研究的逻辑扩展 PI的背侧间充质突出（DMP）。我们将DMP确定为至关重要的结构心室（AV）间充质复合物的发展，并确定DMP得出从第二个心脏场（SHF）。我们提出了一个假设，即DMP可能与 AVSD的发病机理。实际上，在我们对DS模型16（TS16）小鼠的研究研究中，我们发现 AVSD与DMP发育不全有关。此外，我们证明了实验删除据信对于适当的SHF开发至关重要的候选基因（ALK3和SMO）导致扰动 DMP形成和AVSD发病机理。 SHF; SMO小鼠的分析显示了几个包括Sox9的基因。根据我们较早的研究，我们预测Sox9将在DMP中发挥关键作用开发和AV分隔。令人惊讶的是，尽管SHF特异性SOX9删除导致AVSD的50％ SHF; SOX9后代，这不是DMP发育不全的结果，而是与失败的发展有关间充质帽。重要的是，几乎所有被检查的规格都出现了心室间隔缺陷（VSD）。该（已发表）的观察结果与我们对AVSD发病机理的研究结果结合在一起（请参阅：研究计划）导致了有关前SHF和后SHF（ASHF和PSHF）作用的新理论在DS的背景下，心房和心室缺陷的发病机理。我们提出了不同的实验小鼠模型，包括用于检验这些假设的DS的TCMAC21模型。此外，我们将发起单身细胞RNASEQ实验以深入了解与AVSD的发病机理有关的分子机制，特别关注胚胎出口道在VSD发病机理中的作用。