Regeneration and remodeling of collecting lymphatic vessels post-injury

总结

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.