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.

项目摘要/摘要 淋巴管在调节组织流体排水，饮食脂肪吸收和反向方面起关键作用 胆固醇运输。履行这些重要的生理功能需要适当发展 淋巴血管，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淋巴管发生，这可能在 转弯，分别促进癌症转移和同种异体移植排斥。因此，通过 VEGF-C信号传导驱动淋巴管生成不仅会增强对 由淋巴管调节的生理过程，但也有助于发展新型抗 疾病治疗的淋巴管生成策略。我们以前发现淋巴内皮细胞 （LEC）即使在富氧环境中生长，也优先将葡萄糖转化为乳酸。这个独特 代谢特征称为Warburg效应。尽管有这一发现，但仍不清楚是否以及如何 Warburg效应受VEGF-C信号的调节，用于促进发育和病理 淋巴管生成。乳酸脱氢酶A（LDHA）催化丙酮酸还原为乳酸和 氧化烟酰胺腺苷二核苷酸（NAD+）的再生。我们的初步 研究表明，LDHA介导了LEC中的Warburg效应。我们还发现LDHA的遗传消融 小鼠在淋巴血管发育过程中损害LEC增殖和迁移。此外，VEGF-C 增强LEC中的LDHA转录和乳酸产生。这些数据集体支持我们的中心 假设LDHA伴侣VEGF-C信号传导与细胞代谢以驱动淋巴管生成，这 将通过两个具体目标进行测试。 AIM 1将使用遗传小鼠模型和培养的LEC来确定 VEGF-C信号传导在淋巴管中诱导LDHA表达的分子机制 形成。 AIM 2将结合几种高级分析工具，以阐明LDHA的机制 控制细胞代谢以促进淋巴管生成。综上所述，我们提出的研究将确定 LDHA是VEGF-C信号传导与代谢过程之间至关重要的淋巴问题之间的新机械联系 血管形成。我们的工作也可能暗示着一种创新的策略，即通过LDHA针对Warburg效应 抑制作用，用于抑制VEGF-C诱导的病理淋巴管生成。