Regeneration and remodeling of collecting lymphatic vessels post-injury

总结 许多外科手术--如淋巴结清扫和淋巴结活检--都会对淋巴结造成损伤。 淋巴管，特别是当与放疗结合时，导致长期淋巴功能障碍 和水肿的形成。了解手术后淋巴再生的机制， 癌症治疗对于预防水肿和开发有效的水肿疗法至关重要。尽管 水肿的患病率，尚不清楚集合血管是否在损伤后重塑/再生， 这种生长和重塑反应的机制是未知的。淋巴网络的破坏会导致 在剩余的网络中持续的液体负荷导致淋巴功能障碍。抵押不当， 由于持续负荷引起的集合血管重塑可引起适应不良的重塑反应。我瞄准这里 发展淋巴管重塑的理解，修复和功能障碍的背景下， 网络使用复杂的淋巴成像，复杂的小鼠模型和计算建模。我会 研究淋巴流驱动淋巴重塑和再生的机制和模式。我会 测试收集淋巴管是否在损伤后再生/重塑，并确定淋巴流的影响 这一点（目标1）。我还将检验淋巴液流动的改变与 使用遗传小鼠模型激活淋巴管生成途径。此外，我将确定 在我们的小鼠中，在网络中断和淋巴流改变的背景下，损伤部位的侧枝生长 模型（目标2）。我还将使用3D培养系统来研究侧枝生长的动态， 在体外流动和压力条件下收集血管。计算建模将补充目标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。与 完成这个项目后，我将提供深入了解预防战略和更好的治疗干预措施 治疗水肿 我在淋巴生物工程，淋巴成像，图像处理，分离淋巴 容器实验和计算机建模的经验本项目将利用这种培训 在我的博士后导师Padera博士和Munn博士的实验室里，他们是淋巴细胞领域的领导者。 研究和生物学。Padera博士的实验室已经开发出最先进的淋巴成像工具， 动态活体淋巴结显微镜检查及淋巴结动物模型 疾病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图像处理工具来跟踪细胞。这 独特的培训环境将使我能够成功地完成这一建议的目标。

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.