Research

Background on Lymphatic Vessels
 

Lymphatic vessels serve several essential functions in the human body. Lymphatic vessels absorb intestinal lipids, transport immune cells, and return fluid and macromolecules to the blood vasculature. Vessels of the lymphatic system are found in most regions of the body and form a hierarchal network composed of initial and collecting vessels. Initial lymphatic vessels take up excess interstitial fluid through gaps formed between overlapping LECs and transport this fluid to collecting lymphatic vessels. The pumping of collecting lymphatic vessels propels lymph to the thoracic duct, which empties into the venous system. Intraluminal valves in collecting vessels, the thoracic duct, and the lymphovenous junction ensure that lymph moves in an anterograde manner as it is transported through the body. Valve dysfunction and inadequate or excessive growth of lymphatic vessels can impair the ability of the lymphatic network to maintain tissue fluid homeostasis. This can cause lymphatic fluid to accumulate in limbs (lymphedema), the pleural cavity (chylothorax), or in the peritoneal cavity (chylous ascites). Unfortunately, individuals with lymphatic defects have limited therapeutic options and most therapies are palliative in nature. This has fueled intense research efforts to identify the molecular pathways governing the development of the lymphatic vasculature so that new therapies can be developed to treat patients with these devastating defects. 

Research in the Dellinger Laboratory is focused on the lymphatic anomalies Gorham-Stout disease and lymphatic malformation. 

Gorham-Stout disease

Gorham-Stout disease (GSD) is a life-threatening lymphatic anomaly characterized by the presence of lymphatic vessels in bone and the destruction of cortical bone. Despite recent advances in the study of the lymphatic vasculature, the mechanisms driving lymphangiogenesis and osteolysis in GSD remain unknown. This lack of knowledge has prevented the identification of effective therapies and biomarkers for GSD. The overall objective of this project is to use a novel mouse model of GSD developed in our laboratory to gain mechanistic insight into the pathogenesis of GSD. We believe that results from our studies will shed light on the pathogenesis of GSD, provide the rationale for future clinical trials, and contribute to a broader understanding of the mechanisms controlling the formation and regression of lymphatic vessels.

Lymphatic Malformation

Lymphatic Malformation (LM) is a sporadic disease caused by an overgrowth of the lymphatic vasculature. A majority of LMs are apparent at birth and affect the head and neck. These malformations slowly grow larger as the patient grows and can cause severe disfigurement of affected areas. LMs can also impair normal organ function by obstructing or compressing tissues. Somatic activating mutations in PIK3CA were recently found in lymphatic endothelial cells isolated from patients with LM. PIK3CA encodes for the p100α catalytic subunit of PI3K. The goal of this project is to determine the precise mechanism(s) by which excessive PI3K signaling impairs the formation and function of lymphatic vessels. To accomplish this goal, the Dellinger Laboratory is analyzing mice that express an active form of p100α in their lymphatic endothelial cells.