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：
10534652
负责人：
Mohammad Razavi Rizi
金额：
$ 6.95万
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/10534652
关键词：
Accidents Acute Adult Alleles Animal Model Antibodies Antineoplastic Agents Axillary lymph node group Biology Biomedical Engineering Bypass Cannulations Cardiovascular Diseases Cell Culture System Cells Complement Complex Computer Models Cultured Cells Diameter Disease Distal Drainage procedure Endothelium Environment Excision Experimental Models Exposure to Extracellular Matrix Functional disorder Genetic Goals Growth Histology Hydrogels Image Imaging Device Impairment In Vitro Infection Injury Intercellular Fluid Label Length Ligands Ligation Limb structure Liquid substance Lymph Node Dissections 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 Postdoctoral Fellow Prevalence Prevention strategy Process Pump Radiation therapy Reporting Risk Role Route Signal Pathway Signal Transduction Site Structure Surgeon System Testing Therapeutic Intervention Training Trauma VEGFC gene 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 in vitro Model inhibitor 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.

概括许多手术损伤（例如淋巴结清扫和淋巴结活检）可能会对皮肤造成损害。淋巴管，特别是与放疗结合使用时，会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。尽管癌症治疗对于预防淋巴水肿和开发有效的淋巴水肿疗法至关重要。淋巴水肿的患病率，目前尚不清楚受伤后集合血管是否重塑/再生以及这种生长和重塑反应的机制尚不清楚。剩余网络中持续的液体负荷导致淋巴功能障碍和不正确的侧支循环。由于持续负载而收集血管重塑可能会导致适应不良的重塑反应。加深对淋巴管重塑、修复和功能障碍的理解我将使用复杂的淋巴成像、复杂的小鼠模型和计算建模来构建网络。我将研究淋巴流驱动淋巴重塑和再生的机制和模式。测试受伤后集合淋巴管是否再生/重塑并确定淋巴流动的效果我还将测试淋巴流量改变与此反应之间是否存在因果关系。此外，我将确定使用遗传小鼠模型激活淋巴管生成途径的动力学。在我们的小鼠中，在网络和淋巴流动中断的情况下，损伤部位的附带生长模型（目标 2）我还将使用 3D 培养系统来研究现有抵押品增长的动态。体外流量和压力条件下的收集血管计算模型将补充目标 2。更好地理解结构重塑和淋巴流动动力学改变之间的关系。该项目完成后，我将提供有关预防策略和更好的治疗干预措施的见解用于淋巴水肿治疗。我在淋巴生物工程、淋巴成像、图像处理、分离淋巴我的博士培训中的容器实验和计算建模将利用这种培训。在我的博士后导师 Padera 博士和 Munn 博士的实验室里，他们是淋巴领域的领导者帕德拉博士的实验室开发了最先进的淋巴成像工具，可以精确地进行淋巴成像。测量淋巴流速、淋巴结动态活体显微镜检查和淋巴管动物模型 Munn 博士的实验室开发了血管生成的体外模型、血管生成的计算模型。和淋巴运输、生物工程细胞培养系统和跟踪细胞的图像处理工具。独特的培训环境将使我能够成功地完成这个提案的目标。