Metabolic mechanisms controlling lymphatic vessel formation

控制淋巴管形成的代谢机制

• 批准号: 10608206
• 负责人: PENGCHUN YU
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608206
• 关键词: Ablation; Address; Blood Vessels; Cell Proliferation; Cell model; Chemicals; Complex; Cornea; Couples; Data; Development; Dietary Fats; Disease; Drainage procedure; Environment; Equilibrium; Exhibits; FRAP1 gene; Generations; Genetic; Genetic Transcription; Glucose; Glucose-6-Phosphate; Glycolysis; Goals; Health; Hexokinase 2; Impairment; Knowledge; Life; Link; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; MYC gene; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mission; Modeling; Molecular; Mus; NADH; Natural regeneration; Neoplasm Metastasis; Neoplasm Transplantation; Nicotinamide adenine dinucleotide; Nucleotide Biosynthesis; Organ; Organ Transplantation; Oxidation-Reduction; Oxygen; Pathologic; Pentosephosphate Pathway; Pentoses; Physiological; Physiological Processes; Play; Process; Production; Proliferating; Proto-Oncogene Proteins c-myc; Public Health; Pyruvate; Radioisotopes; Research; Role; Signal Induction; Signal Transduction; Testing; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Warburg Effect; Work; absorption; advanced analytics; allograft rejection; analytical tool; cancer therapy; cancer transplantation; cell motility; cell type; genetic approach; genetic manipulation; implantation; innovation; lactate dehydrogenase A; lymphatic development; lymphatic dysfunction; lymphatic vasculature; lymphatic vessel; mouse model; novel; nucleotide metabolism; pharmacologic; programs; reverse cholesterol transport; tumor

PROJECT SUMMARY/ABSTRACT Lymphatic vessels play critical roles in regulating tissue fluid drainage, dietary fat absorption, and reverse cholesterol transport. Fulfilling these important physiological functions requires proper development of the lymphatic vasculature, which is mainly driven by vascular endothelial growth factor C (VEGF-C). VEGF-C signaling also stimulates pathological lymphangiogenesis in tumors and organ transplantation, which may, in turn, promote cancer metastasis and allograft rejection respectively. Therefore, elucidating the mechanisms by which VEGF-C signaling drives lymphangiogenesis will not only enhance the fundamental understanding of physiological processes regulated by lymphatics, but also facilitate the development of novel anti- lymphangiogenic strategies for disease treatments. We previously discovered that lymphatic endothelial cells (LECs), even when grown in an oxygen-rich environment, preferentially convert glucose to lactate. This unique metabolic feature is termed the Warburg effect. Despite this finding, it remains unclear whether and how the Warburg effect is regulated by VEGF-C signaling for promoting developmental and pathological lymphangiogenesis. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and the regeneration of oxidized nicotinamide adenine dinucleotide (NAD+) from its reduced form NADH. Our preliminary studies suggest that LDHA mediates the Warburg effect in LECs. We also found that genetic ablation of Ldha in mice impairs LEC proliferation and migration during lymphatic vascular development. Moreover, VEGF-C enhances LDHA transcription and lactate generation in LECs. These data collectively support our central hypothesis that LDHA couples VEGF-C signaling with cellular metabolism to drive lymphangiogenesis, which will be tested through two Specific Aims. Aim 1 will use genetic mouse models and cultured LECs to determine the molecular mechanisms by which VEGF-C signaling induces LDHA expression during lymphatic vessel formation. Aim 2 will combine several advanced analytical tools to elucidate the mechanisms by which LDHA controls cellular metabolism to promote lymphangiogenesis. Taken together, our proposed studies will identify LDHA as a novel mechanistic link between VEGF-C signaling and metabolic processes critical for lymphatic vessel formation. Our work may also suggest an innovative strategy, i.e., targeting the Warburg effect via LDHA inhibition, for suppressing VEGF-C-induced pathological lymphangiogenesis.

项目总结/摘要 淋巴管在调节组织液排出、膳食脂肪吸收和逆转炎症中起关键作用。 胆固醇转运实现这些重要的生理功能需要适当的发展， 淋巴管系统，其主要由血管内皮生长因子C（VEGF-C）驱动。VEGF-C 信号传导还刺激肿瘤和器官移植中的病理性淋巴管生成， 分别促进肿瘤转移和移植排斥反应。因此，阐明机制， VEGF-C信号驱动淋巴管生成不仅将增强对 生理过程的调节，但也有利于发展新的抗- 用于疾病治疗的淋巴管生成策略。我们之前发现淋巴管内皮细胞 即使在富氧环境中生长，LEC也优先将葡萄糖转化为乳酸。这种独特 这种代谢特征被称为瓦尔堡效应。尽管有这一发现，但仍不清楚是否以及如何 瓦尔堡效应是通过VEGF-C信号调节的，以促进发育和病理 淋巴管生成乳酸脱氢酶A（LDHA）催化丙酮酸还原为乳酸， 氧化的烟酰胺腺嘌呤二核苷酸（NAD+）从其还原形式NADH再生。我们的初步 研究表明LDHA介导LEC中的瓦尔堡效应。我们还发现，Ldha的基因切除， 小鼠在淋巴管发育期间损害LEC增殖和迁移。此外，VEGF-C 增强LEC中LDHA转录和乳酸产生。这些数据共同支持我们的中央 假设LDHA将VEGF-C信号传导与细胞代谢偶联以驱动淋巴管生成， 将通过两个具体目标进行测试。目的1将使用遗传小鼠模型和培养的LEC来确定 VEGF-C信号转导诱导淋巴管中LDHA表达的分子机制 阵目的2将联合收割机几个先进的分析工具，以阐明机制，LDHA 控制细胞代谢以促进淋巴管生成。综上所述，我们建议的研究将确定 LDHA作为VEGF-C信号传导与淋巴细胞关键代谢过程之间的新型机制联系 血管形成我们的工作还可能提出一种创新的战略，即，通过LDHA瞄准瓦尔堡效应 抑制，用于抑制VEGF-C诱导的病理性淋巴管生成。