2016 Research Fellowship Awards

LE&RN announces that it has awarded 2-year research grants ($94,536 USD) to two young researchers who are at the cutting edge of the fight against lymphatic disease and lymphedema. These awards are made possible through a generous bequest from Dorothea M. Weitzner and are called the Henry M. Weitzner, Edna K. Weitzner, Dorothea M. Weitzner and Morton L. Weitzner Research Fellowships. They are designed to expand and strengthen the pool of outstanding junior investigators in the field of lymphatic research. The awards support investigators who have recently received their doctorates, a critical point in career development when young scientists choose their lifelong research focus.
 

Antoine Louveau, Ph.D. University of Virginia, Charlottesville, VA
Regulation of Brain Homeostasis by the Meningeal Lymphatic Vasculature
Until recently, the central nervous system was thought to be devoid of its own lymphatic system. We challenged that dogma by demonstrating the presence of a conventional and functional lymphatic system localized within the central nervous system. This discovery changes our view of normal brain physiology, notably on how does the central nervous system clears its cellular waste. Numerous neurological diseases, including Alzheimer's disease and Parkinson's disease are characterized by the accumulation of misfolded protein inside the brain because of lack of their clearance. In the project, we propose that the meningeal lymphatic system is regulating the clearance of macromolecules from the brain and that dysfunction of the meningeal lymphatic system might drives the accumulation of amyloid beta during Alzheimer's disease. This project overall aims at understanding the biology of the meningeal lymphatic and offers potential therapeutic strategies for lymphatic related neurological disorder.
 

Esak Lee, Ph.D. Wyss Institute at Harvard University, Boston, MA
A Biomimetic on-Chip Model to Reconstitute Lymphedema
Lymphedema is a major lymphatic disorder characterized by swelling tissues. Although poor lymphatic function is closely linked to inflammation, relationship among the lymphatic function, inflammation, and lymphedema is not well understood. We propose to make a "lymphedema-on-chip” that we can study the disease on a nail-size device. Firstly, we will develop a "lymphatics-on-chip" to understand normal lymphatic function without disease. The model will contain a blood capillary, a lymphatic vessel, and lymph fluid to demonstrate fluid leakage from the capillary and resultant lymphatic drainage. Next, we will trigger lymphedema in the normal lymphatics-on chip using inflammatory soluble proteins and matrix proteins to promote lymphedema. Third, we will study the mechanism of lymphedema and treat the disease by prohibiting disease protein signals in the on-chip model and mouse models. This project may contribute to lymphatic community by providing a new 3D lymphedema model as a platform for drug screening and mechanism study.


 

2015 LE&RN/FDRS Lipedema Postdoctoral Fellowship Awards

We are elated to announce that a total of four postdoctoral fellowships were awarded through the inaugural 2015 LE&RN/FDRS Fellowship Program.  The recipients include LE&RN/FDRS Postdoctoral Fellowship Awardees, and due to the generosity of the new Lipedema Foundation, one Lipedema Foundation Postdoctoral Fellowship Awardee.

The LE&RN/FDRS Lipedema Postdoctoral Fellowship Awards Program was developed to stimulate and expand lipedema research, establish its clinical definition, and to understand its pathogenesis.

The Program supports postdoctoral fellows in clinical or basic science research. Fellows must have 3 years or less of full-time postdoctoral experience.  Each applicant must be working under the supervision of an established scientist who is the designated Mentor.

Echoe Bouta, Ph.D.; Massachusetts General Hospital, Boston, MA, United States
Mechanisms of Impaired Lymphatic Function in Mice with Increased Adiposity

Lipedema is a chronic disorder that is characterized by painful swelling restricted to the lower limbs caused by increased fat stores that even a strict diet regimen is typically unable to eliminate. While lipedema is a prevalent disease, little is known about what causes it and therefore, treatment of lipedema patients is often ineffective. Clinical studies suggest that lipedema patients have lymphatic system dysfunction and reduced immune function, as they are unable to clear infections effectively. Therefore, we will determine how lymphatic vessel and immune function changes in mice with increased fat stores. We will next determine what molecules cause lymphatic dysfunction. Finally, we will then increase lymphatic function by targeting a pathway known to be important to lymphatic vessel contraction as improving lymphatic function is a potential therapy for lipedema patients. This study will provide critical knowledge about the mechanism of lipedema progression and test potential therapies.  Mentor:  Timothy Padera, Ph.D.


Rachelle Crescenzi, Ph.D.; Vanderbilt University, Nashville, TN, United States
Functional Imaging of Sodium and Lymphatics in Patients with Lipedema

Lipedema is a chronic and incurable condition estimated to effect up to 11% of the female population. The disease is characterized by a thickening of the subcutical adipose tissue, which is often painful, and is likely hereditary. It is frequently underdiagnosed, or misdiagnosed as lymphedema or obesity. The critical barrier to diagnosing lipedema rests with a lack of tools for assessing specific features of the disease without invasive procedures. In this study, we propose to use novel magnetic resonance imaging methodologies to develop markers of lipedema, including impaired processing of lymph fluid in the legs and accumulation of sodium in the skin. If successful, this work will aid our understanding of the cause of disease, and allow for the development of novel therapies.  Mentor:  Manus J. Donahue, Ph.D.


Javier Jaldin-Fincati, Ph.D.; The Hospital for Sick Children, Toronto Ontario, Canada
Communication Between Adipose and Lymphatic Microvascular Endothelial Cells

We hypothesize that products of adipocyte metabolism may affect the correct function of lymphatic microvascular endothelial cells (L-MEC), contributing to Lipedema. We think that if lymphatic capillaries do not drain 'toxic materials' out of adipose tissue, such as fatty acids, an inflammation state is generated. If we add to this an insufficient removal of excess insulin, a vicious cycle may ensue of insulin resistance in fat cells and inflammation in the tissue that will further damage lymphatic capillaries.

In this context, it is essential investigate the effect of increased levels of insulin and fatty acids on metabolism and viability of L-MEC. To address that, we propose isolate L-MEC from human adipose tissue and cultivate them under normal and pathological levels of adipocyte metabolites and insulin. This will lead to a better understanding of how these cells respond to healthy and sick environments created by adipose tissue.  Mentor:  Amira Klip, Ph.D.


Annalisa Zecchin, Ph.D.; University of Leuven, VIB, Leuven, Belgium
Novel Metabolite-Based Treatment Approach of Lymphedema: Possible Relevance for Lipedema?

Lipedema, the accumulation of lipids within the extremeties, is a debilitating disorder whose underlying cause is not understood, and currently has no curative treatments. Lymphedema, the accumulation of fluid in the extremeties, is better understood, and has been suggested to be linked to lipedema. In this proposal, we will explore whether altering nutrient availability can promote lymphatic function to improve lymphedema, and possibly lipedema.  Mentor:  Peter Carmeliet, M.D., Ph.D.

 

2014 Research Fellowship Awards:

Functional Characterization of Primary Lymphedema Gene GATA2

Lymphatic vasculature constitutes a network of vessels critical for the maintenance of tissue fluid homeostasis. Failure of the lymphatic system leads to chronic swelling, called lymphedema, but it is also linked to defects in immune function, obesity, atherosclerosis and cardiovascular disease. This project aims to further our understanding of the pathophysiological mechanisms involved in lymphedema by investigating the function of GATA2 transcription factor, a newly identified causative gene of primary lymphedema. Towards this aim, researchers will characterize the in vivo role of Gata2 in lymphatic development and identify molecular and cellular mechanisms by which Gata2 regulates lymphangiogenesis. They will use state-of-the-art conditional knockout mouse models established in the laboratory that allow specific and temporally controlled deletion of Gata2 in lymphatic vasculature. Complementarily, they will analyze the Gata2 controlled genetic program and cellular functions using cultured lymphatic endothelial cells isolated from mutant mice or human tissues. This study will provide fundamental novel insights into normal lymphatic development and pathophysiology of lymphedema. This knowledge is expected open up new therapeutic approaches for the treatment of lymphedema and other lymphatic disorders.

Characterization of Novel Modulator of Vegfc/Vegfr3 Signaling during Lymphatic Development

The lymphatic vasculature comprises of a network of vessels that serve primarily to maintain tissue fluid homeostasis. Malfunction of lymphatic vessels leads to lymphoedema, which can be primary (inherited) or secondary (acquired). The formation of new lymphatic vessels is a central process in these pathologies and requires VEGFC/VEGFR3 singling pathway. Studies in the zebrafish have uncovered new and conserved regulators of lymphangiogenesis, enhancing our understanding of lymphatic development and the genetic basis of lymphoedema.  One such key regulator was Ccbe1, an extracellular-matrix protein that is essential regulator of Vegfc/Vegfr3 signalling to promote lymphatic vessel formation, and when mutated in humans causes generalised lymphoedema (Hennekam syndrome). Our laboratory investigates the genetic factors that cause inherited lymphedema and that control formation of new lymphatic vessels.

In the genetic screen that the host PI identified the ccbe1 mutation, we also identified another novel mutant dubbed lymphatic and facial defects 1 (lyf1). Utilising two independent genetic approaches, we have shown that lyf1 is a regulator of the Vegfc signalling pathway during development. Here, we will study the role of this new gene in detail. This will allow us to better understand the formation of lymphatic vasculature and should serve as an avenue to find new therapeutic targets and approaches in lymphedema and vascular diseases.

Genetic Basis of the Yellow Nails-Lymphedema-Pleural-Effusion Syndrome

This research seeks to identify the gene that causes autosomal recessive Yellow Nail-Lymphedema-Pleural-Effusion Syndrome.

Interacation Between Lymphatic Vessels and Secondary Lymphoid Organs in Development

This research seeks to provide a better understanding of the roles of lymphatic vessels in the development of the immune system, and provide new information important for the pathogenesis and treatment of lymphatic diseases, lymphedema, and related disorders.

Molecular Photoacoustic Imaging Using Multitarged Contrast Agents

This research seeks to provide an increased understanding of the interactions between solid tumors and the surrounding lymphatic system.

Development of Transcriptional Differentiation Approaches For Treatment of Lymphedema-Distichiasis Syndrome

Research increased knowledge of the regulation of vascular specification during vertebrate development and sought to design novel treatment strategies for primary and secondary lymphedema.

Development and Maintenance of Lymphatic Endothelial Cell Specializations in Mouse Respiratory Tract

This research expanded knowledge of the structure and function of specialized lymphatic endothelial junctions in development, health, and disease.

Genetic Analysis of Lymphatic System Development in Zebrafish

Research offered insights into the genetic progrmas and celluar behaviors that help shape the lymphatic vasculature.

Molecular Biology and Therapeutic Potential of Multipotent Adult Progenitor Cell (MAPC) Derived Lymphatic Endothelial Cells

Investigation of RhoB's Function in Lymphatics: a Model to Improve Lymphedema Therapy

Near-Inrared Fluorescence Optical Imaging of Lymph Function in a Preclinical Murine Model

Lymphangiogenesis in Acute and Chronic Models of Inflamation

Functional Roles of Myosin Light Chain in Lymphatic Pumping Activity

Xenopus Laevis as a Model to Study Lymphangiogenesis in Health and Disease

Lineage Tracing to Identify the Sources of Lymphatic Endothelial Cells

The Role of Tie2 and the Angiopoietins in EPC Biology

Click here for more details on these studies.