Pathobiology of lymphatic function: in vivo near-infrared lymphatic imaging

淋巴功能的病理学：体内近红外淋巴成像

• 批准号: 10023173
• 负责人: Yang Lee
• 金额: $ 1.55万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023173
• 关键词: Adaptor Signaling Protein; Adult; Alleles; Animal Model; Attenuated; Biochemical; Biological Assay; Blood Vessels; Cell Differentiation process; Cells; Chronic; Chyle; Co-Immunoprecipitations; Coupled; Data; Development; Diagnostic; Disease; Edema; Embryo; Enhancers; Exhibits; FOXC2 gene; Functional disorder; Genetic; Genetic Transcription; Goals; Health; High Fat Diet; Homeostasis; Human; Immune; Immunoblotting; Impairment; In Vitro; Inflammation; Insulin Resistance; Intestines; Investigation; Lipids; Liquid substance; Luciferases; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic System; Lymphedema; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Natural regeneration; Near-infrared optical imaging; Obese Mice; Obesity; Pathogenesis; Pathologic; Pathway interactions; Patients; Physiological; Predisposition; Reporter; Role; Signal Transduction; Testing; Therapeutic; Tissues; Transcriptional Activation; Transgenic Animals; VEGFC gene; Vascular Endothelial Growth Factor Receptor-3; absorption; attenuation; combat; epsin; gain of function; imaging approach; improved; in vivo; innovation; loss of function; lymph flow; lymphatic imaging; lymphatic vessel; new therapeutic target; novel; promoter; regenerative; restoration; targeted treatment; tool; trafficking; transcription factor; uptake

Project Summary/Abstract The lymphatic system, with its intrinsic physiologic functions in cellular homeostasis, immune cell trafficking, and lipid absorption, contributes significantly to the pathogenesis of metabolic disorders. Lymphatic dysfunction shows strong positive correlation with obesity and results in increased susceptibility to lymphedema. Defective lymphatic vessels by lacking one allele of Prox1, a transcription factor that regulates lymphatic endothelial cell differentiation, induces adult-onset obesity, suggesting that lymphatic dysfunction directly contributes to the development of metabolic disorders. In contrast, metabolic diseases exhibit lymphatic dysregulation that contributes to the development of further pathological conditions including inflammation, impaired lipid absorption, or elevated chyle accumulation coupled with increased susceptibility of edema. However, how lymphatic dysfunctions aggravate metabolic diseases, and conversely, how metabolic disorders induce lymphatic dysfunctions are unknown but highly relevant medical questions. Our preliminary data show that deficiency of Foxc2, a critical regulator of lymphangiogenesis, elevates VEGFR3 signaling and causes an increase in lymphangiogenesis both in vivo and in vitro. In addition, loss of lymphatic endothelial Foxc2 enhanced collecting lymphatic function and lymph flow in adult mice. Hence, we will identify 1) the therapeutic potential of targeting Foxc2 in lymphatic dysfunction in metabolic disorders and 2) the underlying molecular mechanisms by which Foxc2 regulates adult lymphangiogenesis and lymphatic function. Using the innovative conditional lymphatic endothelial specific Foxc2 gain-of-function or Foxc2 loss-of-function mice, we will test the direct role of Foxc2 in pathophysiological lymphatic regeneration and function in metabolic diseases. In addition, we will utilize highly sensitive NIR imaging approaches to assess in vivo lymph transport in our live transgenic animals. Finally, we will determine underlying molecular mechanisms by which Foxc2 regulates lymphangiogenesis and lymphatic function. We will use Chip, immunoblotting, co-immunoprecipitation, and luciferase reporters to complete this in- depth investigation. Thus, this proposal will identify important targets that modulate lymphangiogenesis and lymphatic function in mature lymphatic vessels, which could potentially provide diagnostic tools or therapies to improve lymph transport and, consequently mitigate lymphatic dysfunctions in patients with Metabolic Syndrome or secondary lymphedema.

项目摘要/摘要 淋巴系统，由于其内在的生理功能，在细胞内稳态，免疫细胞运输，和 脂质吸收，在代谢紊乱的发病机制中起着重要作用。淋巴功能障碍 显示出与肥胖有很强的正相关性，并导致淋巴水肿的易感性增加。有缺陷的 淋巴管缺乏调节淋巴管内皮细胞转录因子Prox1的一个等位基因 分化，导致成人发作性肥胖，表明淋巴功能障碍直接导致 代谢紊乱的发展。相比之下，代谢性疾病表现为淋巴调节失调 有助于进一步的病理状况的发展，包括炎症，脂质吸收受损， 或乳糜液堆积增加，同时增加了对水肿的易感性。然而，淋巴有多大 功能障碍会加重代谢性疾病，反过来，代谢性疾病又是如何导致淋巴循环的 功能障碍是未知的，但具有高度相关性的医学问题。我们的初步数据显示， 淋巴管生成的关键调节因子FOXC2上调VEGFR3信号并导致血管生成增加 体内和体外的淋巴管生成。此外，淋巴管内皮细胞FOXC2的丢失增强了收集 成年小鼠的淋巴功能和淋巴流量。因此，我们将确定1)靶向治疗的潜力 FOXC2在代谢紊乱淋巴功能障碍中的作用以及2)其潜在的分子机制 FOXC2调节成人淋巴管生成和淋巴功能。使用创新的条件淋巴管 内皮细胞特异性FOXC2功能获得或丧失小鼠，我们将测试FOXC2在 代谢性疾病中淋巴管的病理生理再生和功能。此外，我们还将高度利用 灵敏的近红外成像方法评估我们的活体转基因动物体内的淋巴运输。最后，我们 将确定FOXC2调节淋巴管生成和淋巴管的潜在分子机制 功能。我们将使用芯片、免疫印迹、免疫共沉淀和荧光素酶记者来完成这项工作- 深入调查。因此，这项提议将确定重要的靶点，调节淋巴管生成和 成熟淋巴管的淋巴功能，这可能提供诊断工具或治疗 改善淋巴转运，从而缓解代谢综合征患者的淋巴功能障碍 或继发性淋巴水肿。