Kar Lai Pang

Research Project Title: Investigating the role of PlexinD1 in lymphatic valve development and lymphoedema

Research Summary

Lymphoedema is a chronic and debilitating condition characterized by tissue swelling in the extremities and can be life-threatening. To date, there is no cure for lymphoedema and the treatments options are limited to physical therapy, massage and compression garments, which only provide symptomatic relief. Primary lymphoedema is clinically and genetically heterogeneous and affects approximately 1 in 6000 people. Patients with primary lymphoedema find it debilitating and stressful; often are suffering from significant psychological distress. Our understanding of genetic and molecular mechanisms leading to lymphoedema development is scarce, highlighting the urgent need for research in this area.

Lymphatic valve (LV) defects are a common feature of lymphoedema. Regularly spaced LVs are derived from lymphatic endothelial cells (LECs) and are crucial for forward lymph flow; in turn, lymph flow is critical for the development and lifelong maintenance of LVs. Shear stress is, therefore, a critical determinant of LV development. However, the molecular mechanisms of how LECs sense and respond to lymph flow and hence turn on the LV programme to generate functional valves are poorly understood. Our group has recently discovered a novel mechanosensor that is capable of sensing blood flow in arterial endothelial cells. Using genetic knockout mouse model, deletion of this protein in the LECs leads to lymphatics valve defect, while the mutation in this gene are associated with lymphoedema in patients.

Biography

Since my doctoral training, I have cultivated a deep interest in the developmental processes of the cardiovascular system, particularly in understanding how mechanical forces shape organ and vasculature development. During my doctoral study, I focused on dissecting the mechanisms by which alterations in hemodynamics lead to defective cardiac valves in chick embryonic hearts. Following my PhD, I continued to pursue my research interest by joining Professor Ellie Tzima's mechanotransduction group at the University of Oxford, where I investigated how the mechanical stimulus of blood flow impacts cardiovascular function. I have now embarked a new area of research, studying how mechanical forces shape the development and function of the lymphatic system.

The BHF CRE Transition Fellowship allows me to investigate the fundamental mechanisms that lead to the development of lymphoedema. I hope to be able to secure external intermediate fellowship in near future.