A Critical Role for Leukotriene B4 in Lymphedema

白三烯 B4 在淋巴水肿中的关键作用

• 批准号: 10322667
• 负责人: Mark Robert Nicolls
• 金额: $ 49.72万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322667
• 关键词: Address; Affect; Antigen Presentation; Applications Grants; Arachidonate 5-Lipoxygenase; Back; Biology; Biophysics; Biopsy; Blood; Blood Circulation; Cancer Survivor; Cell Survival; Cells; Chronic; Clinical; Clinical Trials; Data; Dendritic Cells; Disease; Drug Targeting; Exposure to; Future; Genes; Genetic; Goals; Grant; Growth; Human; Immune; Immunity; Immunophenotyping; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Leukotriene B4; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Mediating; Medical; Metabolism; Microcirculatory Bed; Molecular; Nature; Neuropilin-2; Paper; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phenotype; Physiological; Property; Publishing; Pump; RNA; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Role; Sampling; Signal Pathway; Signal Transduction; Skin; Surveys; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transcript; Ubenimex; Vascular Endothelial Growth Factor Receptor-3; Vascular remodeling; Work; cell growth; cell injury; curative treatments; design; effective therapy; efficacy testing; immunoregulation; in vivo; lipid mediator; lymphatic circulation; lymphatic pump; notch protein; pre-clinical; repaired; skin disorder; sphingosine 1-phosphate; synthetic enzyme; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; tumor-immune system interactions; ward

PROJECT SUMMARY / ABSTRACT Lymphedema is a chronic and debilitating condition currently without approved medical therapies. Recent investigations suggest a central role for inflammation in this disease. We discovered that leukotriene B4 (LTB4), a critical lipid mediator of inflammation, promotes lymphatic endothelial cell (LEC) sprouting and growth at low concentrations (10nM), and causes LEC injury at high concentrations (200nM) by differentially affecting two essential lymphatic survival pathways, VEGFR3 and Notch. During pre-clinical lymphedema progression, lymphatic fluid LTB4 concentrations rise from initial pro-lymphangiogenic concentrations, into an anti- lymphangiogenic range which may induce pathology. Anti-LTB4 therapy reverses pre-clinical lymphedema. This finding is the scientific basis for a Phase 2 clinical trial (ULTRA), which is currently testing the efficacy of LTB4-targeted therapy for lymphedema. New results from a separate proof-of-concept clinical trial are positive, making this the first effective medicinal therapy for this condition. Even though anti-LTB4 therapy may be helpful for lymphedema, it is likely not curative, and more information is needed to understand how inflammatory pathways promote disease. Studies proposed in the grant are designed to address fundamental mechanistic questions about how LTB4 damages lymphatic capillaries and promotes a proinflammatory microenvironment. Our global hypothesis is that after lymphatic injury, increased LTB4 exacerbates lymphedema by inhibiting key lymphatic growth pathways, interfering with the (blood) microvascular circulation, transforming LECs and redirecting the immune microenvironment. To address these issues, this proposal is divided into three Specific Aims as follows. Aim 1 is to study the mechanisms by which LTB4 alters pro-lymphangiogenic signaling pathways, causes blood vascular remodeling and changes LEC cellular identity. Aim 2 will investigate how LTB4 impacts the immune microenvironment in lymphedema by influencing the activation and phenotype of proinflammatory dendritic cells and T lymphocytes and by changing lymphatic immunoregulatory functions. Finally, Aim 3 will use omic technologies to evaluate clinical lymphedema samples collected by the ULTRA trial to assess the genetic networks built around LTB4 biology in lymphedema. The goals of these studies are to understand the molecular mechanisms of reparative lymphangiogenesis, the plasticity of LEC identify and the dynamics of immune regulation in lymphedema. By carefully assessing the immune microenvironment and the global transcriptome in lymphedema, it should be possible to evolve better drug therapies for this pervasive and, otherwise, unremitting condition.

项目摘要/摘要

项目成果

Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience.

• DOI: 10.1002/ctm2.760
• 发表时间: 2022-04
• 期刊: CLINICAL AND TRANSLATIONAL MEDICINE
• 影响因子: 10.6
• 作者: Rockson, Stanley G.;Zhou, Xin;Zhao, Lan;Hosseini, Davood K.;Jiang, Xinguo;Sweatt, Andrew J.;Kim, Dongeon;Tian, Wen;Snyder, Michael P.;Nicolls, Mark R.
• 通讯作者: Nicolls, Mark R.

Colorectal Cancer-Associated Microbiome Patterns and Signatures.

• DOI: 10.3389/fgene.2021.787176
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Zhao L;Cho WC;Nicolls MR
• 通讯作者: Nicolls MR

The Human Respiratory Microbiome: Current Understandings and Future Directions.

• DOI: 10.1165/rcmb.2022-0208tr
• 发表时间: 2023-03
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4

Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.

• DOI: 10.1016/j.chest.2021.06.028
• 发表时间: 2021-10
• 期刊: Chest
• 影响因子: 9.6
• 作者: Sweatt AJ;Miyagawa K;Rhodes CJ;Taylor S;Del Rosario PA;Hsi A;Haddad F;Spiekerkoetter E;Bental-Roof M;Bland RD;Swietlik EM;Gräf S;Wilkins MR;Morrell NW;Nicolls MR;Rabinovitch M;Zamanian RT
• 通讯作者: Zamanian RT

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

淋巴 S1P 信号异常会加剧淋巴功能障碍和组织炎症。

• DOI: 10.1101/2023.06.08.23291175
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Kim,Dongeon;Tian,Wen;Wu,TimothyTing-Hsuan;Xiang,Menglan;Vinh,Ryan;Chang,Jason;Gu,Shenbiao;Lee,Seunghee;Zhu,Yu;Guan,Torrey;Schneider,EmilieClaire;Bao,Evan;Dixon,JBrandon;Kao,Peter;Pan,Junliang;Rockson,StanleyG;Jiang,Xin
• 通讯作者: Jiang,Xin