Defining the mechanisms of lymphatic and lymphovenous valve development

定义淋巴管和淋巴静脉瓣发育的机制

• 批准号: 9194206
• 负责人: Rajanarayanan S Srinivasan
• 金额: $ 44.2万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194206
• 关键词: Ablation; Adult; Agonist; Anatomy; Binding Sites; Biological Assay; Blood Circulation; Blood Vessels; Cell Differentiation process; ChIP-seq; Complex; Coupled; Cytoplasm; Data; Defect; Development; Disease; Endothelial Cells; Enhancers; Fibrosis; Figs - dietary; Gene Activation; Gene Expression; Genes; Genetic; Health; Human; Hypertension; Knowledge; Lead; Ligands; Limb structure; Link; Liquid substance; Lymph; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphedema; Malignant Neoplasms; Mechanics; Mediating; Mission; Modeling; Molecular Profiling; Mus; Nuclear Translocation; Obesity; Palliative Care; Pathway interactions; Patients; Regulatory Element; Role; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Stimulus; Structure; Structure of jugular vein; Structure of subclavian vein; Swelling; Testing; Therapeutic; Time; Transcription Coactivator; Transgenic Organisms; Translating; Work; beta catenin; chromatin immunoprecipitation; fluid flow; gain of function; genetic information; human disease; in vivo; innovation; insight; loss of function; mouse model; novel; novel strategies; novel therapeutics; prevent; primary lymphedema; receptor; shear stress; small molecule; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT In healthy adult humans the lymphatic vasculature collects as much as 12 liters of lymph per day. Defects in lymphatic vascular function lead to lymphedema, which is characterized by the swelling of limbs. Additional health problems caused by lymphedema include fibrosis, hypertension, obesity and even cancer. While palliative treatments are available, they are never curative. Barriers to advancing new therapies include a remarkably limited present understanding of lymphatic functional anatomy and genetic controls. Lymph collected by lymphatic vessels is transported through collecting lymphatic vessels in which lymphatic valves prevent fluid stasis. Finally, lymph is returned to the blood circulation via four lymphovenous valves. Defects in lymphatic or lymphovenous valves are associated with lymphedema. The objective of this application is to better define the mechanisms of valve development, which remain poorly understood and is a critical barrier for treating lymphedema. We have determined that Wnt/β-catenin signaling pathway is necessary for the development of lymphatic and lymphovenous valves. Building on key preliminary data we will attempt to identify the upstream activators and downstream targets of Wnt/β-catenin signaling pathway. Numerous agonists and antagonists of Wnt/β-catenin signaling pathway are available. Therefore, our findings could translate into innovative approaches to treat human lymphedema patients.

项目总结/文摘