Dissecting the functional roles of cardiac lymphatics in ischemic heart disease

总结 心肌梗死（MI）是全球发病率和死亡率的主要原因。因此，寻求新的 治疗方法仍然是该领域的优先事项。最近的研究表明，刺激淋巴 缺血性心脏病后的生长（淋巴管生成）可改善心脏功能， 心脏重塑和心脏淋巴管生成可能通过改善心脏损伤后的修复， 炎症反应的清除。此外，我发表的作品揭示了一个新的附加 一种“主动的”，促生存旁分泌信号（淋巴管分泌，Reelin）从淋巴细胞 内皮细胞促进损伤后心肌细胞（CM）存活，这一结果挑战了传统观点， 流体输送作为流体输送的“被动”途径。然而，详细的机制， 增加的淋巴管生成改善心脏修复还没有被完全理解。我们令人兴奋的初步数据 提示淋巴管生成促进心脏修复需要心脏保护性淋巴管分泌 信号和高效的淋巴免疫清除功能。该提案旨在利用各种有价值的 动物模型，以确定心脏修复过程中心脏淋巴管生成的这些功能作用。在 目的1的建议，我们将确定的分子途径和目标如何心脏淋巴管生成 改善MI后CM存活率。在本提案的目标2中，我们的目标是使用各种淋巴损失-和增益- 功能小鼠品系，以详细描述心脏修复期间的淋巴功能，并确定 这些最佳效果在治疗缺血性疾病中的治疗潜力。这些基本发现 将影响包括淋巴生物学和心血管研究在内的多个领域，最终目标是 确定治疗心血管疾病的新靶点。

SUMMARY Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Therefore, seeking new therapeutic approaches is still the priority in the field. Recent studies have shown that stimulation of lymphatic growth (lymphangiogenesis) after ischemic heart disease improves cardiac function and attenuates adverse cardiac remodeling, and cardiac lymphangiogenesis likely improves heart repair after injury by improving the clearance of inflammatory response. Furthermore, my published work has unraveled a novel additional mechanism that an “active”, pro-survival paracrine signaling (lymphoangiocrine, Reelin) from lymphatic endothelial cells promotes cardiomyocyte (CM) survival after injury, a result challenging the traditional view that lymphatics function as a “passive” route for fluid transport. However, the detailed mechanism/s by which increased lymphangiogenesis improves heart repair is not yet fully understood. Our exciting preliminary data suggest that lymphangiogenesis improves cardiac repair requires both, cardioprotective lymphoangiocrine signals and efficient lymphatic immune clearance function. This proposal is set out to use a various valuable animal models to determine these functional roles of cardiac lymphangiogenesis during cardiac repair. In the Aim 1 of the proposal, we will determine the molecular pathways and targets how cardiac lymphangiogenesis improve CM survival after MI. In the Aim 2 of this proposal, we aim to use a variety of lymphatic loss- and gain- of function mouse strains to characterize in details the lymphatic functions during cardiac repair, and determine the therapeutic potential of these optimal effects in treatment of ischemic disease. These fundamental findings will impact diverse fields including lymphatic biology and cardiovascular research, with an ultimate goal to identify novel targets for the treatment of cardiovascular diseases.