Regeneration and remodeling of collecting lymphatic vessels post-injury

损伤后集合淋巴管的再生和重塑

基本信息

批准号：
10156902
负责人：
Mohammad Razavi Rizi
金额：
$ 6.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156902
关键词：
Acute Adult Alleles Animal Model Antibodies Antineoplastic Agents Axillary lymph node group Biology Biomedical Engineering Bypass Caliber Cardiovascular Diseases Cell Culture System Cells Complement Complex Computer Models Cultured Cells Disease Distal Drainage procedure Endothelium Environment Excision Exposure to Extracellular Matrix Functional disorder Genetic Goals Growth Histology Hydrogels Imaging Device Impairment In Vitro Infection Injury Intercellular Fluid Label Lead Length Ligands Ligation Limb structure Liquid substance Lymph Node Dissections Lymphangiogenesis Lymphatic Lymphatic Diseases Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic Obstruction Lymphatic Research Lymphatic System Lymphatic function Lymphedema Maintenance Malignant Neoplasms Measures Mediating Microfluidics Modeling Mus Muscle Cells Natural regeneration Near-infrared optical imaging Operative Surgical Procedures Optical Coherence Tomography Organ Pathway interactions Patients Pharmacotherapy Phenotype Phosphorylation Play Prevalence Prevention strategy Process Pump Radiation therapy Reporting Risk Role Signal Pathway Signal Transduction Site Structure Surgeon System Testing Therapeutic Intervention Training Trauma Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor D Vascular Endothelial Growth Factor Receptor-3 Western Blotting angiogenesis cancer surgery cancer therapy curative treatments density experimental study image processing imaging genetics in vitro Model inhibitor/antagonist insight intravital microscopy lymph flow lymph node biopsy lymph nodes lymphatic circulation lymphatic dysfunction lymphatic imaging lymphatic vessel migration mouse model novel therapeutic intervention pressure prevent repaired response secondary lymphedema shear stress three dimensional cell culture tool

项目摘要

SUMMARY Many surgical insults—such as lymph node dissection and lymph node biopsy —can cause damage to the lymphatic vessels, particularly when combined with radiotherapy, resulting in long-term lymphatic dysfunction and the formation of lymphedema. Understanding the mechanisms of lymphatic regeneration after surgery and cancer treatment is crucial to prevent lymphedema and develop efficient lymphedema therapy. Despite the prevalence of lymphedema, it is not clear whether collecting vessels remodel/regenerate post-injury and mechanisms of such growth and remodeling response are unknown. A disrupted lymphatic network induces sustained fluid loads in the remaining network that drives lymphatic dysfunction. Improper collateralization and collecting vessel remodeling due to sustained loads can cause a maladaptive remodeling response. Here I aim to develop an understanding of lymphatic vessel remodeling, repair and dysfunction in the context of a disrupted network using sophisticated lymphatic imaging, complex mouse models, and computational modeling. I will investigate the mechanisms and modes by which lymph flow drives lymphatic remodeling and regrowth. I will test whether collecting lymphatic vessels regrow/remodel following injury and determine the effect of lymph flow on this response (Aim 1). I will also test whether there is a causal relationship between altered lymph flow and activation of lymphangiogenic pathways using genetic mouse models. Further, I will determine the dynamics of collateral growth at the injury site in the context of a disrupted network and altered lymph flow in our mouse model (Aim 2). I will also use a 3D culture system to study the dynamics of collateral growth from pre-existing collecting vessels under flow and pressure conditions in vitro. Computational modeling will complement Aim 2 to better understand the relationship between structural remodeling and alteration of lymph flow dynamics. With the completion of this project, I will provide insight into preventive strategies and better therapeutic interventions for lymphedema therapy. I have extensive training in lymphatic bioengineering, lymphatic imaging, image processing, isolated lymphatic vessel experiments and computational modeling from my doctoral training. This project will leverage this training in the labs of my postdoctoral advisors—Dr. Padera and Dr. Munn—who are leaders in the field of lymphatic research and biology. Dr Padera’s lab has developed state-of-the-art lymphatic imaging tools to precisely measure lymph flow rate, dynamic intravital microscopy of lymph nodes and animal models of lymphatic diseases. Dr Munn’s lab has developed in vitro models of angiogenesis, computational models of angiogenesis and lymphatic transport, bioengineered cell-culture systems and image processing tools to track cells. This unique training environment will allow me to successfully complete the aims of this proposal.

概括许多手术侮辱（例如淋巴结清扫和淋巴结活检）可能会损害淋巴血管，特别是与放射疗法结合时，导致长期淋巴功能障碍以及淋巴水肿的形成。了解手术后淋巴再生的机制癌症治疗对于预防淋巴水肿和发展有效的淋巴水肿至关重要。尽管有淋巴水肿的患病率，尚不清楚收集船只改造/再生后伤害后和这种生长和重塑反应的机制尚不清楚。淋巴网络中断会引起剩余的网络中持续的流体负荷驱动淋巴功能障碍。不正确的抵押和收集由于持续负荷而导致的血管重塑会导致适应不良的重塑反应。我在这里在中断的情况下，要了解淋巴血管重塑，修复和功能障碍使用复杂的淋巴成像，复杂的鼠标模型和计算建模的网络。我会研究淋巴流动驱动淋巴重塑和改革的机制和模式。我会测试受伤后是否遗憾/改造收集淋巴视频并确定淋巴流的影响关于此响应（目标1）。我还将测试淋巴流量改变和使用遗传小鼠模型激活淋巴管途径。此外，我将确定在网络中断的背景下，损伤部位的附带生长和小鼠的淋巴流动改变了模型（AIM 2）。我还将使用3D培养系统研究附带的生长动态。在体外收集血管和压力条件下的容器。计算建模将完成目标2 更好地了解结构重塑和淋巴流动动力学改变之间的关系。和该项目的完成，我将洞悉预防策略和更好的治疗干预措施用于淋巴水肿疗法。我在淋巴生物工程，淋巴成像，图像处理，孤立的淋巴处理方面进行了广泛的培训我的博士培训的船只实验和计算建模。该项目将利用此培训在我的博士后顾问的实验室中， Padera和Munn博士 - 是淋巴领域的领导者研究与生物学。 Padera博士的实验室已经开发了最先进的淋巴成像工具来精确测量淋巴结的淋巴流量，淋巴结的动态浸泡显微镜和淋巴动物模型疾病。 Munn博士实验室开发了血管生成的体外模型，即血管生成的计算模型以及淋巴运输，生物工程细胞培养系统和图像处理工具以跟踪细胞。这独特的培训环境将使我能够成功完成该提案的目标。