2015 MDBR Funds 3 Studies
The Lymphangiomatosis & Gorham’s Disease Alliance (LGDA) and the Lymphatic Malformation Institute (LMI) are proud to announce the three projects selected to receive the LGDA-LMI 2015 MDBR Rare Disease Research Grants. The LGDA and LMI joined together Saturday, May 9, 2015, in Philadelphia to participate in the 2nd Annual Million Dollar Bike Ride. Together the teams raised more than $100,000, which the Orphan Disease Center at University of Pennsylvania matched dollar-for-dollar, bringing the total available for research to $203,000.
We congratulate the 2015 awardees and are making plans to participate in the MDBR in May 2016 in order to continue funding research important to better understanding lymphangiomatosis and Gorham’s disease.
Lymphatic Imaging and Intervention Center at The Children’s Hospital of Philadelphia
University of Pennsylvania
Project: Dynamic Contrast Enhanced MR Lymphangiogram Imaging of Lymphatic Anomalies
The Lymphatic Imaging and Intervention Center at The Children’s Hospital of Philadelphia, received a $101,000 grant for the purpose of imaging the lymphatic system. Specifically, the study aims to demonstrate thoracic lymphatic anatomy in patients with lymphangiomatosis/Generalized Lymphatic Anomaly (GLA), Gorham-Stout disease (GSD), or Kaposiform Lyphangiomatosis (KLA) using heavy weighted T2 MR and Dynamic Contrast-Enhanced MR Lymphangiogram (DCMRL) to better understand lymphatic anatomy and lymph fluid flow in patients with Lymphatic Anomalies.
The major cause of mortality and morbidity in these patients is the deterioration of pulmonary function by chronic chylous effusions and progressive interstitial lung disease. The understanding of changes in patients’ pulmonary lymphatic anatomy is hindered by the difficulty of imaging of the lymphatic system.
DCMRL is a technique that has recently been developed, allowing dynamic MR imaging of the lymphatic system by injecting gadolinium contrast agent into the lymph nodes in the patient’s groin to perform imaging instead of gaining access from the foot, as in traditional lymphangiogram. Focusing on imaging of the deep lymphatic vessels in chests of patients with these rare lymphatic malformations and pulmonary involvement of the disease will enable the team to gain understanding of how these deranged lymphatics behave in the chest and their impact on pulmonary function.
Co-directors of the Center are Dr. Maxim Itkin and Dr. Yoav Dori who have dedicated their careers to the development of advanced, non-invasive methods to image the lymphatic system. Dr. Itkin is the principal investigator on this project. Study participants will be recruited through the International LGDA Registry for Lymphatic Malformations.
David Cormode, PhD
University of Pennsylvania
Project: Nano-magnetic Oils for the Study of Intestinal Lymphatics in Lymphangiomatosis
Lymphangiomatosis/Generalized Lymphatic Anomaly (GLA) is a condition where abnormally proliferating lymphatic vessels cause disruption to organs such as the intestines, liver, lungs and bone. The lymphatic vessels coming from the intestine are a key part of the lymphatic system and are frequently involved in lymphangiomatosis/GLA. One of the main issues with understanding, diagnosing and treating lymphangiomatosis/GLA is the lack of methods to visualize lymphatic vessels; and of all lymphatic systems, the intestinal lymphatics particularly lack imaging approaches.
This study seeks to develop a new contrast agent using iron oxide-labeled oils that will be administered orally so iron oxides can be taken up and distributed into the intestinal lymphatic vessels via chylomicrons, thereby allowing for the visualization of intestinal lymphatics using magnetic resonance imaging (MRI). The contrast agent will be fed to healthy mice and to mice that have lymphangiomatosis. The mice will undergo MRI to measure the effectiveness of the contrast in visualizing the intestinal lymphatic vessels. Successful uptake of the nano-magnetic oils into the intestinal lymphatics will allow for the visualization of these vessels that is necessary to facilitate the development of treatments and enhance our understanding of the disease.
Dr. Cormode’s research focuses on the development of novel and multifunctional nanoparticle contrast agents for medical imaging applications.
Joseph Rutkowski, PhD
Texas A&M Health Science Center School of Medicine
Project: Inducible Lymphatic Hyperplasia to Drive Chylous Accumulation Mimicking Lymphangiomatosis
The process of lymphatic endothelial cell hyperproliferation (an abnormally high rate of cell division) results in the increase in both the size and number of lymphatic vessels observed in lymphangiomatosis/Generalized Lymphatic Anomaly (GLA). VEGF-D is a type of protein that is a powerful driver of lymphatic proliferation. Dr. Rutkowski’s lab has developed a novel mouse line in which it has induced the over-expression of VEGF-D, producing massive and deranged lymphatic expansion in the mice resulting in chyloascites and the eventual, lethal chylothorax mimicking lymphangiomatosis/GLA.
One advantage of this drug-inducible transgenic system is that it is dose-dependent. Dr. Rutkowski’s lab will be further characterizing this dose dependence, seeking to identify early peripheral manifestations, such as increased tissue fluid accumulation that might precede chylothorax. The lab will also seek to identify the dietary fatty acids and changes in lymph composition that specifically amplify VEGF-D signaling effects.
With the ability to tightly control lymphatic proliferation, Dr. Rutkowski’s lab proposes that the results of this study will provide a novel platform to study the manifestation and therapeutic maintenance of lymphangiomatosis.
Since the beginning of his PhD studies, Dr. Rutkowski’s research has focused on lymphatic vessel biology, lymphangiogenesis, and the physiology of lymphatic diseases. His recent work has focused on developing new genetic mouse models that permit specific manipulations of lymphatic endothelial cell biology. The funded project will support an exciting and potentially clinically-relevant new model that may provide a novel platform on which to test the manifestation of lymphangiomatosis/GLA, disease progression, and potential remediation.
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