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Cardiac Lymphatics in Development and Repair

心脏淋巴管的发育和修复

基本信息

批准号：
10852321
负责人：
Kathleen M Caron
金额：
$ 25.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10852321
关键词：
3-Dimensional Address Administrative Supplement Affect Animal Model Aortic Valve Stenosis Attenuated Biological Models Blood Cardiac Cardiac health Cardiovascular Diseases Cardiovascular system Cause of Death Cells Clinical Research Defect Development Disease Echocardiography Elderly Endothelial Cells Endothelium Event Fibrosis Functional disorder G Protein-Coupled Receptor Signaling Genetic Goals Heart Heart Valve Diseases Heart Valves Heart failure Histology Image Knowledge Ligands Light Lymphatic Lymphatic Endothelial Cells Lymphatic Endothelium Mesenchymal Microscopy Mind Molecular Molecular Target Mus Myocardium National Heart, Lung, and Blood Institute Pathologic Patients Phenotype Population Process Profibrotic signal Prognostic Marker Proliferating RNA Reporter Research Role Signal Transduction Specificity Sudden Death Testing Ventricular adrenomedullin cadherin 5 cell type chemokine receptor coronary fibrosis heart function mouse model novel peptide hormone receptor repaired response semilunar valve single-cell RNA sequencing transcriptomics

项目摘要

Abstract With cardiovascular disease the leading cause of death worldwide, valvular heart disease (VHD) currently affects 2.5% of the US population and is one of the most important factors responsible for cardiovascular disease events. Even more surprising, a large-scale clinical study found previously undiagnosed VHD in 50% of the elderly population, further accentuating the need for a better understanding of the pathophysiology of VHDs. However, VHDs remain understudied, and the underlying pathological mechanisms are poorly characterized. Adrenomedullin (AM), a peptide hormone with numerous cardiovascular roles, has been recently shown as the most potent prognostic biomarker in aortic stenosis. Moreover, the AM decoy receptor, Atypical Chemokine Receptor 3 (ACKR3) also attenuates pro-fibrotic signaling and ACKR3-deficient mice display severe valvular defects, including thickened semilunar valves due to increased proliferation of the semilunar valve mesenchymal cells, and develop ventricular fibrosis. Nevertheless, the role of AM and its decoy receptor in cardiac valve development or function has yet not been investigated in detail. With this knowledge in mind, we hypothesize that endothelial and endocardial AM - ACKR3 signaling is a key player in regulating cardiac valvulogenesis and aberrant cardiac fibrosis. Using state-of-the-art light-sheet microscopy, single- cell RNA transcriptomic and animal model approaches, we propose to build on our current expertise GPCR signaling to broad our knowledge on how AM - ACKR3 signaling modulates cardiac health. Our studies will expand our understanding of the underlying molecular mechanisms leading to valvular defects and cardiac fibrosis formation and uncover possible molecular targets for patients with valvular heart diseases.

抽象的心血管疾病是全世界死亡的主要原因，瓣膜性心脏病 (VHD) 目前影响 2.5% 的美国人口，是最重要的因素之一负责心血管疾病事件。更令人惊讶的是，一项大规模的临床研究发现 50% 的老年人患有先前未诊断的 VHD，进一步强调了需要更好地了解 VHD 的病理生理学。然而，VHD 仍然存在尚未得到充分研究，并且其潜在的病理机制也知之甚少。肾上腺髓质素 (AM) 是一种具有多种心血管作用的肽激素，最近被研究被证明是主动脉瓣狭窄最有效的预后生物标志物。此外，AM 诱饵受体，非典型趋化因子受体 3 (ACKR3) 也会减弱促纤维化信号传导， ACKR3缺陷小鼠表现出严重的瓣膜缺陷，包括半月瓣增厚增加半月瓣间质细胞的增殖，并发展心室纤维化。尽管如此，AM 及其诱饵受体在心脏瓣膜发育或功能尚未详细研究。考虑到这些知识，我们假设内皮和心内膜 AM - ACKR3 信号传导是调节心脏的关键因素瓣膜形成和异常心脏纤维化。使用最先进的光片显微镜，单细胞 RNA 转录组和动物模型方法，我们建议以我们目前的 GPCR 信号传导专业知识，扩大我们对 AM - ACKR3 信号传导如何调节的知识心脏健康。我们的研究将扩大我们对潜在分子的理解导致瓣膜缺陷和心脏纤维化形成的机制并揭示可能的瓣膜性心脏病患者的分子靶点。