Examination of a new mouse model of mitral valve disease

项目摘要 瓣膜性心脏病(VHD)，最常见的与二尖瓣脱垂(MVP)有关，导致 严重的反流导致心脏骤停或心源性猝死。二尖瓣内皮细胞 (ECS)是建立二尖瓣结构的关键参与者，对维持二尖瓣结构是必不可少的 二尖瓣的完整性和功能。然而，二尖瓣内皮细胞控制结构的机制 二尖瓣病变在MVP进展过程中的变化尚未得到充分的描述。长的- 本提案的术语目标是阐明规范EC在廉洁和 了解二尖瓣功能的改变，并了解这些机制的破坏是如何导致MVP的。 FOXC1和FOXC2是Fox转录因子家族中关系密切的成员，有许多 在心血管发育、健康和疾病中的重要作用。有证据表明人类FOXC1. 突变与二尖瓣畸形有关，包括二尖瓣关闭不全。我们之前已经 在小鼠中，Foxc1和/或FOXC2的全局纯合敲除突变与血管相关 异常；然而，突变也会导致胚胎或围产期死亡，所以试图确定 这两个foxc基因在成年动物中的作用通常还没有定论。为了克服这一限制，我们 产生了一系列携带他莫昔芬诱导的EC特异性化合物Foxc1的小鼠；FOXC2突变(即EC- Foxc-DKO小鼠)，而Parent奖旨在阐明Foxc1/FOXC2在血管修复和修复中的作用 直接调节CXCL12和R-pondin 3旁分泌基因表达对损伤后肠再生的影响 肠道内皮细胞的影响因素。在为家长奖执行拟议研究的过程中，使用 Foxc-DKO小鼠，我们还获得了对这些成年突变体的初步研究结果，这些突变体 表明成人的Foxc1/c2突变损害了心脏二尖瓣的结构和完整性。 因此，我们的中心假设是二尖瓣内皮细胞中foxc1/c2的转录活性与二尖瓣病变有关。 阀门的完整性和功能。我们将通过追求两个具体目标来检验我们的中心假设：(1) 确定二尖瓣内皮细胞是否需要FOXc1和FOXC2才能使二尖瓣正常发育 以及(2)确定Foxc1和FOXC2的EC表达调节完整性和 二尖瓣的功能。总而言之，本提案中描述的实验将提供至关重要的 二尖瓣EC人群中Foxc1/c2缺陷是如何导致二尖瓣缺陷的信息 作为MPV。此外，由于二尖瓣的损伤会导致各种心脏疾病，我们的发现 可能对与VHD相关的其他病理情况，如心力衰竭，具有重要的意义。

Project Summary Valvular heart disease (VHD), which is most commonly associated with mitral valve prolapse (MVP), causes severe regurgitation leading to sudden cardiac arrest or sudden cardiac death. Mitral valve endothelial cells (ECs) are crucial participants in establishing mitral valve structures and are essential for the maintenance of mitral valve integrity and function. However, the mechanisms by which mitral valve ECs govern structural changes in the mitral valve during the progression of MVP have yet to be adequately characterized. The long- term goal of this proposal is to elucidate the fundamental processes that regulate EC function in the integrity and function of the mitral valve and to understand how the disruption of these mechanisms leads to MVP. FOXC1 and FOXC2 are closely related members of the FOX transcription factor family and have numerous essential roles in cardiovascular development, health, and disease. There is some evidence that human FOXC1 mutations are associated with mitral valve abnormalities, including mitral regurgitation. We have previously shown that in mice, global homozygous knockout mutations of Foxc1 and/or Foxc2 are associated with vascular anomalies; however, the mutations also lead to embryonic or perinatal lethality, so attempts to determine how the two Foxc genes function in adult animals have generally been inconclusive. To overcome this limitation, we generated a line of mice carrying tamoxifen-inducible, EC-specific, compound Foxc1;Foxc2 mutations (i.e., EC- Foxc-DKO mice), and the parent award is aimed at elucidating the role of Foxc1/Foxc2 in vascular repair and intestinal regeneration after injury by directly regulating the expression of CXCL12 and R-spondin 3 paracrine factors in intestinal ECs. During the course of performing the proposed studies for the parent award using the Foxc-DKO mice, we also obtained the results from preliminary investigations with these adult mutants, which indicate that the Foxc1/c2 mutations in the adult impair the structure and integrity of the mitral valve of the heart. Thus, our central hypothesis is that the transcriptional activity of Foxc1/c2 in mitral valve ECs contributes to mitral valve integrity and fucntion. We will test our central hypothesis by pursuing the two Specific Aims: (1) To determine whether Foxc1 and Foxc2 are required in mitral valve ECs for proper development of the mitral valve and (2) To determine the mechanisms by which EC expression of Foxc1 and Foxc2 regulates the integrity and function of the mitral valve. In summary, the experiments described in this proposal will provide crucial information about how Foxc1/c2 deficiency in mitral valve EC populations contributes to mitral valve defects such as MPV. Furthermore, since impairments in the mitral valve contribute to various cardiac disorders, our findings may have important implications for other pathologic conditions associated with VHD such as heart failure.