LRF Postdoctoral Fellowship Class of 2012–2014

Three outstanding young researchers have been selected for the LRF Postdoctoral Fellowship grants for the 2012–2014 grant cycle. Selected from a field of well-qualified applicants, the following recipients and their research projects are representative of exciting developments in lymphatic investigations.

Molecular Photoacoustic Imaging using Multitargeted Contrast Agents. Critical to improving the treatment of cancer is an increased understanding of the interactions between solid tumors and the surrounding lymphatic system. Lymphangiogenesis and cancer metastasis are the result of a complex interaction between the constituents of the tumors, including the tumor cells and the cells of the vasculature and lymphatics. The ability to noninvasively image the lymphatics before and after the treatment of an in vivo tumor model could provide information critical to understanding the treatment mechanism. Therefore, in vivo imaging studies of tumor response to treatment while monitoring the lymphatic, vascular and tumor anatomy, could lead to improved therapeutic techniques for cancer. To address this need, we propose to use the multiplex photoacoustic molecular imaging system being developed to study the lymphatics surrounding the described tumors while following the proposed treatment plans. Recent experimental results from this project have demonstrated the accumulation of two targeted nanorods contrast agents within in vivo tumors with differing cellular receptor overexpression. Current work seeks to improve bioconjugation methods to enhance the in vitro cellular uptake of the silica-coated gold nanorod contrast agents, and to reduce the overall size of the gold nanorods via novel chemical synthesis methods. To address the question of the impact of lymphatic involvement in the tumor growth and treatment response, we propose the following minor modification to our future studies. In addition to targeting HER2/neu and α_vβ₃integrin, we will add a third silica-coated gold nanorod contrast agent bioconjugated to a monoclonal antibody specific to the lymphatic endothelial hyaluronan receptor-1 (LYVE-1). Multispectral photoacoustic images will be acquired, and the resulting photoacoustic signals will be spectrally unmixed to distinguish the location of each unique contrast agent, correlating to the anatomical locations of the tumor cells, the lymphatics, and the vasculature. The tumors will be monitored for a change in the density of the lymphatics and vasculature supplying the tumor region, in response to treatment, using our multiplex photoacoustic imaging system. The resulting images will demonstrate proof of principle photoacoustic molecular imaging of both lymphatics and vasculature in vivo under therapeutic treatment. This unique approach would enable the study of the interactions between vasculature infiltration, lymphangiogenesis, and tumor cell growth and response to treatment in vivo to provide critical insight on the effect tumor treatment on lymphangiogenesis and lymphatic regression.

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Carolyn Bayer, PhD, University of Texas at Austin Mentor: Stanislav Emelianov

Genetic Basis of the Yellow Nails-Lymphedema-Pleural Effusion Syndrome (OMIM 153300). Yellow nail syndrome (YNS) is a rare disorder of unknown cause characterized by lymphedema, yellow nails and chronic respiratory manifestations. The aims of this proposal are 1) to identify the gene that causes autosomal recessive Yellow Nail-Lymphedema-Pleural Effusion (YNS; OMIM 153300) using a combination of homozygosity mapping and next generation sequencing in a large Jordanian kindred; 2) to test for heterogeneity of the YNS syndrome in three other consanguineous families from the Middle East to see if their YNS is caused by the same mutation, by other mutations in the same gene, or is caused by mutations in another gene by direct sequencing of the gene in other families and singleton cases from the same population: and 3) to test whether YNS appearing as a sporadic in populations from the United States and Europe is caused by mutation in the YNS gene identified in the Middle Eastern population, or mutation in a different gene by direct sequencing of the YNS gene in patient from the United States and Europe. This will identify a new gene causing heritable lymphedema, characterize the genetic heterogeneity within the YNS syndrome, and will be the first identified lymphedema gene that leads to highly penetrant lung phenotype, pleural effusion, that may give us an entry to the study of the role of the lymphatics in the lung. We will also attempt to characterize the role of the YNS gene through a series of gene expression studies and immunohistochemical studies in human and mouse skin and lung biopsies.

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Alireza Haghighi Kakhki, MD, PhD, University of Pittsburgh, PA/Wellcome Trust Centre for Human Genetics, UK Mentor: Robert E Ferrell, PhD

The Interaction between Lymphatic Vessels and Secondary Lymphoid Organs in Development. Secondary lymphoid organs play a unique and crucial role in the organization and function of the adaptive immune system, and are the site where T cells recognize the antigens presented by dendritic cells (DCs) and other antigen presenting cells (APCs) to activate the adaptive immune response.

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Yiqing Yang, PhD, University of Pennsylvania Mentor: Mark Kahn, MD

Lymphatic vessels play an essential role in secondary lymphoid tissue function and adaptive immunity, as efferent and afferent lymphatic vessels connect the relatively solitary lymph nodes with the lymphatic system: afferent lymphatic vessels transport antigens and APCs from distant regions to lymph nodes (LNs), while efferent lymphatic vessels provide the route by which lymphocytes enter LNs and Peyer's patches (PPs) to search for their cognate APC and re-enter the vasculature to fulfill their effector function.

Efficient adaptive immune responses rely upon the ability of the lymphatic vascular network to interface with and support secondary lymphoid tissues, but the roles of lymphatic vessels in the development of secondary lymphoid organs have not been well studied.

Our laboratory has recently generated mice lacking CCBE1, a novel lymphangiogenic factor responsible for human Hennekam syndrome and required for all lymphatic growth in mice. These mice exhibit a complete lack of lymphatic vessels with no defects in other organs or blood vessels, and therefore are an ideal model in which to dissect the role of lymphatic vessels during LN and PP formation and maintenance.

In this proposal I will use these newly generated CCBE1 knockout and conditional knockout animals and studies of the development of LNs and PPs to address these important questions. In my PhD studies I focused on immunology studies of T cell development, a background that is strongly complementary to the expertise in lymphatic vascular development in the Kahn lab and that will allow me to integrate the vascular and immune biology in this proposal. These studies are predicted to provide a better understanding of the roles of lymphatic vessels in the development of immune system, and give us new information important for the pathogenesis and treatment of lymphatic diseases, lymphedema and related disorders.

We are pleased to welcome these three outstanding young researchers to our growing list of LRF Fellows who are advancing the boundaries of lymphatic science and biology. We applaud the excellent work of the LRF Postdoctoral Scientific Review Committee Chair, Mihaela Skobe, PhD, Associate Professor Oncological Sciences, Mount Sinai School of Medicine, and Committee members Reza Dana, MD, MPH, MSc, Claes H. Dohlman Professor of Ophthalmology and Vice Chairman and Associate Chief of Ophthalmology, Massachusetts Eye & Ear Infirmary; Michael J. Davis, PhD, Margaret Poctor Mulligan Professor in Medical Research, Medical Pharmacology & Physiology, University of Missouri; Mark Kahn, MD, Professor of Medicine, University of Pennsylvania Translational Research Center; Jan Kitajewski, PhD, Charles and Marie Robertson Professor, Department of Pathology and Ob/Gyn, Columbia University; and Nancy Ruddle, PhD, John Rodman Paul Professor Emerita, Department of Epidemiology and Public Health and Department of Immunobiology, Yale University School of Medicine. Congratulations and our heartfelt thanks to all!

LRF 2012 Walk Brings Out Patients, Families, Researchers, and Medical Professionals to Raise Funds for Research

LRF's September 15^th Annual Lymphedema and Lymphatic Disease Walk at Eisenhower Park, Long Island, NY marked our third successful walkathon event. It's not too late to support a Walk Team or make an individual contribution. Go to www.walklrf.org to donate and to see our sponsor list.

A First for Lymphatic Research and Biology

We are enormously grateful to Mihaela Skobe, PhD for serving as Guest Editor for this first special section of Lymphatic Research and Biology dedicated to the lymphatic system and cancer. Bringing her expertise in cancer research and imaging as well as her astute editing and leadership skills, Dr. Skobe has helped to create a truly milestone issue of Lymphatic Research and Biology!

As advancements in lymphatic biology are increasingly impacting multiple research and medical disciplines (oncology a major area among many), we applaud the decision of the Lymphatic Research and Biology editorial board to dedicate select future issues to particular disciplines and topics. We are excited to learn that future issues will be planned with a focus on Immunology, AIDS and Autoimmune Diseases, Diabetes, and more. We express our gratitude to editor-in-chief, Stanley Rockson, MD, and publisher Mary Ann Liebert for their visionary insight in planning future growth for Lymphatic Research and Biology.