Cardiac Lymphatics in Development and Repair

摘要 心血管疾病是全球死亡的主要原因， (VHD)目前影响着2.5%的美国人口，是最重要的因素之一， 导致心血管疾病事件。更令人惊讶的是，一项大规模的临床研究 在50%的老年人中发现了以前未诊断的VHD，进一步加重了 需要更好地了解VHD的病理生理学。然而，VHD仍然 研究不足，潜在的病理机制也很难描述。 肾上腺髓质素（AM）是一种具有多种心血管作用的肽类激素， 显示为主动脉瓣狭窄中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（ACKR 3）也减弱促纤维化信号传导， ACKR 3缺陷小鼠显示严重的瓣膜缺陷，包括由于 增加半月瓣间充质细胞的增殖， 纤维化尽管如此，AM及其诱饵受体在心脏瓣膜发育中的作用， 功能尚未详细研究。有了这些知识，我们假设， 内皮细胞和内皮细胞AM-ACKR 3信号传导在调节心脏的 瓣膜形成和异常心脏纤维化。使用最先进的光片显微镜，单个- 细胞RNA转录组学和动物模型方法，我们建议建立在我们目前的 专业知识GPCR信号转导，以扩大我们对AM-ACKR 3信号转导如何调节 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 心脏瓣膜病患者的分子靶点。

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.