Projects Funded in 2015
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.
Projects Funded in 2016
Andrea Del Fattore, PhD, and Andrea Bartuli, MD
Bambino Gesù Children’s Hospital, Rome, Italy
Project: Understanding the molecular and cellular defects of bone remodeling in patients affected by Gorham-Stout disease (GSD)
Gorham-Stout disease (GSD) is a rare bone disorder characterized by progressive osteolysis and angiomatous proliferation, without new bone formation. At the onset of the disease, x-ray analysis may reveal a patchy osteoporosis condition; later complete bone loss may occur, resulting in the appearance of the so-called “vanishing bone” disease. The mechanisms underlying the excessive bone resorption are not entirely known. The diagnosis is challenging and is usually the result of ruling out neoplastic processes, infection, and metabolic and endocrine disorders.
Small structures called Extracellular Vesicles (EV) are increasingly recognized to play a pivotal role in cell-to-cell communication. EV are released by many cells, including osteoblasts and osteoclasts, and recently have been subject to intense investigations into the potential use of circulating EV for the diagnosis of different disease states.
This study seeks to identify alterations of bone remodeling activity in GSD patients and to investigate the involvement of extracellular vesicles in the bone phenotype and their possible use as novel diagnostic and/or prognostic biomarkers.
Dr. Del Fattore is the Head of Bone Physiopathology Laboratory at Bambino Gesù Children’s Hospital in Rome. He obtained his Bachelor’s and Master’s degrees in Biotechnology at “Sapienza” University of Rome developing his thesis on bone diseases. He got his PhD degree in 2009 at University of L’Aquila (Italy). Dr Del Fattore takes part in international scientific committees. He obtained several awards and honors, including the ECTS Iain T Boyle Award, a prestigious award for young scientists who have made significant progress and contribution to the field of bone and calcified tissue. The research activity of Dr Del Fattore is focused on the study of bone diseases.
Dr. Bartuli graduated in Medicine (1984) and specialized in Pediatrics (1985) at the University of Rome, he is a full time pediatrician at the Academy Department of Pediatric of Bambino Gesù Children’s Research-Teaching Hospital of Rome and Head of the Rare Diseases and Genetic Unit. He is President of Società Italiana Malattie Genetiche Pediatriche [and] Disabilità Congenite (SIMGePeD).
Carrie Shawber, PhD.
Columbia University Medical Center, New York, NY
Project: Identification of the Genetic Causes of Generalized Lymphatic Anomalies
Generalized Lymphatic Anomaly (GLA) is a rare multi-focal lymphatic anomaly that is difficult to diagnose and commonly misidentified. GLA complications can involve multiple organs and anatomic areas, with chylothorax, chylous ascites, and lytic bony lesions. However, these morbidities are also found in other lymphatic disorders that have been empirically categorized: Gorham-Stout disease (GSD) and kaposiform lymphangiomatosis (KLA). It is unclear if GLA, GSD, and KLA constitute a spectrum of one disorder, or if they are distinct conditions, as the underlying genetic defects are unknown. The lack of understanding of the genetic underpinnings of these diseases limits development of diagnostics and novel therapeutics.
This translational research project will use lymphatic endothelial cell lines generated from GLA specimens for genetic analysis to relate genotype to phenotype in GLA. These studies have the potential to identify new genes and pathways that function in lymphatic development and homeostasis. The goal of this project is to gain information that will lead to increasingly precise diagnostic information that will aid clinicians in identifying and characterizing GLAs.
Dr. Shawber is Assistant Professor in Reproductive Sciences in Ob/Gyn and Surgery, Columbia University Medical Center, New York, NY. Her laboratory is interested in understanding developmental and pathological lymphatic vascular biology. In collaboration with Dr. June Wu, a plastic surgeon with a research program focused on vascular anomalies of the blood vasculature in the Department of Surgery, they have developed a basic and translational vascular anomalies research program to characterize and identify the causes of vascular anomalies. Dr. Shawber’s translational research program aims to improve our understanding into lymphatic anomalies and identify optimal treatment options.
Projects Funded in 2017
J. Brandon Dixon, PhD
George W. Woodruff School of Mechanical Engineering – Emory University and Georgia Tech
Project: Tissue Engineered Lymphatic Malformation on a Chip for Screening Therapeutics
Denise Adams, MD
Harvard University School of Medicine, Boston, MA
Project: Retrospective analysis of the safety and efficacy of lymphatic anomalies of the bone (Generalized Lymphatic anomaly (GLA), Gorham Stout Disease (GSD), Channel type Lymphatic Malformation (CTLM)) treated with mTOR inhibition and bisphosphonates
Projects Funded in 2018
Shoshana Greenberger, MD PhD
Sheba Medical Center and Tel-Aviv University, Israel
Project: Role of NRAS mutations in the pathology of generalized lymphatic anomaly (GLA)
Andrea Del Fattore, PhD
Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Project: Analysis of crosstalk between regulatory T and bone cells in Gorham-Stout