Molecular mechanisms enhancing lymphatic valve formation

增强淋巴瓣形成的分子机制

• 批准号: 10543483
• 负责人: Ying Yang
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543483
• 关键词: Ablation; Adipose tissue; Adult; Affect; Animal Model; Cancer Patient; Cancer Survivor; Chronic; Chronic Disease; Connexin 43; DNA Sequence Alteration; Data; Deposition; Disease; Disease model; Economic Burden; Embryo; Excision; Exhibits; FOXC2 gene; FOXO1A gene; FRAP1 gene; Fibrosis; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Growth; Heterozygote; Human; Immune response; Impairment; Innovative Therapy; Knockout Mice; Laboratories; Liquid substance; Lymph; Lymph Node Dissections; Lymphangiography; Lymphatic; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Maintenance; Mediating; Modeling; Molecular; Molecular Target; Morphology; Mus; Near-infrared optical imaging; Outcome; PIK3CG gene; Pathologic; Pathway interactions; Patients; Persons; Phenotype; Prevention strategy; Repression; Role; Signal Pathway; Signal Transduction; Swelling; Symptoms; Tamoxifen; Testing; Time; Tissues; Western Blotting; cancer therapy; druggable target; effective therapy; human model; inhibitor; insight; lymph flow; lymph nodes; lymph stasis; lymphatic valve; lymphatic vasculature; lymphatic vessel; mTOR Signaling Pathway; mouse model; new therapeutic target; novel; pharmacologic; postnatal; pressure; prevent; recurrent infection; response; shear stress; small molecule; targeted treatment; transcription factor

Lymphedema is a chronic disease that is caused by a dysfunctional lymphatic vasculature, and can occur from either genetic mutations or physical damage. The disease affects 3-5 million people in the US alone, and the majority are cancer survivors who had lymph node removal surgery. There are no effective treatments for lymphedema, nor any prevention strategies. Symptoms include severely swollen tissues due to adipose tissue deposition and fibrosis, resulting in an impaired immune response and recurring infections in patients. Numerous studies have established that chronic lymph stasis begets lymphedema. Impaired lymph flow in mice causes the regression of lymphatic valves because constant flow-mediated signals are required for the formation and ongoing maintenance of lymphatic valve leaflets. Further, forward lymph flow is maintained only by regularly spaced intraluminal valves derived from lymphatic endothelial cells (LEC). Lymphangiography of human patients with either congenital or acquired lymphedema is characterized by retrograde lymph flow, which strongly implicates defective or regressing lymphatic valves as a causative factor. Thus, a significant unmet need is to prevent lymphatic valve regression and/or stimulate lymphatic valve formation to treat lymphedema. Surprisingly little is known about how valve-forming genes are activated in response to fluid shear stress. We have identified the first transcription factor that acts as a repressor of lymphatic valve formation, Foxo1, and show that genetic deletion of Foxo1 from LEC increases the number of lymphatic valves significantly. Our data are the first to show that the ablation of any gene is capable of increasing the number of morphologically normal lymphatic valves. Thus, inhibitors of the Foxo1 pathway represent highly valuable pharmacologic targets to enhance valve formation. Our central hypothesis is that deletion of Foxo1 will increase the number of lymphatic valves by upregulating known valve-forming genes and will restore valve function in an animal model of lymphedema. This hypothesis will be tested by the following three aims: Aim 1 will determine the mechanisms by which loss of Foxo1 enhances lymphatic valve formation, Aim 2 will identify Foxo1-associated signaling pathways that increase lymphatic valve formation, and Aim 3 will  analyze the function of lymphatic valves in healthy and lymphedematous mice lacking Foxo1. It is highly anticipated that these aims will provide novel insights into the role of Foxo1 in regulating valve formation and function, which will ultimately lead to the identification of a druggable target and innovative therapy to treat patients with lymphedema by augmenting valve growth and function.

淋巴水肿是一种慢性疾病，是由功能失调的淋巴管系统，并可能发生， 要么是基因突变要么是身体损伤这种疾病仅在美国就影响了300万至500万人， 大多数是接受淋巴结切除手术的癌症幸存者。没有有效的治疗方法 水肿，也没有任何预防策略。症状包括严重肿胀的组织由于脂肪组织 沉积和纤维化，导致患者免疫应答受损和反复感染。 许多研究已经证实，慢性淋巴结淤滞引起水肿。淋巴液流动受损 小鼠引起淋巴阀的退化，因为需要恒定的流动介导的信号， 淋巴瓣叶的形成和持续维持。此外，仅维持前向淋巴流 通过来自淋巴管内皮细胞（LEC）的规则间隔的管腔内瓣膜。淋巴管造影 患有先天性或获得性水肿的人类患者的特征在于逆行淋巴流， 其强烈暗示有缺陷的或退化的淋巴瓣是致病因素。因此，一个重要的 未满足的需求是防止淋巴瓣退化和/或刺激淋巴瓣形成以治疗 水肿令人惊讶的是，人们对瓣膜形成基因是如何响应流体而被激活的知之甚少。 剪应力我们已经确定了第一个转录因子，作为一个阻遏淋巴阀 形成，Foxo 1，并显示从LEC中基因缺失Foxo 1会增加淋巴阀的数量， 显著我们的数据首次表明，任何基因的切除都能够增加 形态正常的淋巴瓣。因此，Foxo 1途径的抑制剂代表了高度有价值的 增强瓣膜形成的药理学靶点。我们的中心假设是，Foxo 1的缺失将导致 通过上调已知的瓣膜形成基因来增加淋巴瓣膜的数量， 在水肿动物模型中的作用。这一假设将通过以下三个目标进行检验： 将确定Foxo 1缺失增强淋巴阀形成的机制，Aim 2将确定 Foxo 1相关的信号通路，增加淋巴阀的形成，和目标3将分析 Foxo 1缺失的健康和水肿小鼠的淋巴管功能。备受期待的是， 这些目标将为Foxo 1在调节瓣膜形成和功能中的作用提供新的见解， 将最终导致确定一个可药用的目标和创新的治疗方法，以治疗患者 通过增加瓣膜生长和功能引起的水肿。

项目成果

Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor.

• DOI: 10.1016/j.immuni.2021.10.003
• 发表时间: 2021-12-14
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Czepielewski RS;Erlich EC;Onufer EJ;Young S;Saunders BT;Han YH;Wohltmann M;Wang PL;Kim KW;Kumar S;Hsieh CS;Scallan JP;Yang Y;Zinselmeyer BH;Davis MJ;Randolph GJ
• 通讯作者: Randolph GJ

Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model.

• DOI: 10.3389/fcell.2022.1024628
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5

Protocol for in vivo and in vitro study of lymphatic valve formation driven by shear stress signaling pathway.

• DOI: 10.1016/j.xpro.2023.102141
• 发表时间: 2023-04-17
• 期刊: STAR PROTOCOLS
• 作者: Banerjee, Richa;Knauer, Luz A.;Yang, Ying
• 通讯作者: Yang, Ying

VEGFR3 is required for button junction formation in lymphatic vessels.

• DOI: 10.1016/j.celrep.2023.112777
• 发表时间: 2023-07-25
• 期刊: Cell reports
• 影响因子: 8.8

VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development.

• DOI: 10.7554/elife.77241
• 发表时间: 2022-04-29
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Sung, Derek C.;Chen, Xiaowen;Chen, Mei;Yang, Jisheng;Schultz, Susan;Babu, Apoorva;Xu, Yitian;Gao, Siqi;Keller, T. C. Stevenson;Mericko-Ishizuka, Patricia;Lee, Michelle;Yang, Ying;Scallan, Joshua P.;Kahn, Mark L.
• 通讯作者: Kahn, Mark L.