Dissecting the functional roles of cardiac lymphatics in ischemic heart disease

剖析心脏淋巴管在缺血性心脏病中的功能作用

• 批准号: 10585972
• 负责人: XIAOLEI LIU
• 金额: $ 47.03万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-13 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585972
• 关键词: Address; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Attenuated; Biology; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Death Induction; Data; Development; Disease; Engraftment; Genes; Goals; Growth; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Immune response; Impairment; Inflammatory Response; Injury; Ischemia; Knowledge; Lead; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic function; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Paracrine Communication; Pathway interactions; Publishing; Recombinant Proteins; Regulation; Reporting; Research; Role; Route; Signal Transduction; Therapeutic; Time; VEGFC gene; Vascular Endothelial Growth Factor C; Work; cardiac repair; cardioprotection; coronary fibrosis; gain of function; heart function; heart preservation; immune cell infiltrate; immune clearance; immune function; improved; loss of function; lymphatic drainage; lymphatic vasculature; mitochondrial dysfunction; mortality; mouse model; novel; novel therapeutic intervention; repaired; transcriptome sequencing

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.

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会通过改善心脏的功能来改善损伤后的心脏修复。 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”、促生存的旁分泌信号（淋巴管分泌，Reelin）从淋巴细胞中发出的机制， 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。