Unlike its sister hemovascular system, the lymphatic circulation largely escapes preclinical and clinical investigation owing to the limited methods available to non- invasively image lymphatic architecture and function. The lack of in vivo lymphatic imaging severely limits our ability to understand lymphatic biology in preclinical models, to evaluate lymphatic components of human disease of increasing prevalence, and to stratify hereditary lymphatic diseases for efficient genotyping. Moreover, there is sparse understanding of the physiological responses of lymphatic function in both health and disease. In this application, we seek to develop functional 2-D lymph imaging as well as 3-D lymph angiography using near-infrared (NIR) time independent and dependent techniques and associated imaging agents. We seek to evaluate lymphatic architecture and physiologic responses in health and disease and more importantly, to develop an important and missing imaging tool for lymphatic research. Specifically, our aims are to: (1) Demonstrate human imaging of lymphatic function and its physiological response in normal subjects and patients who suffer from lymph dysfunction using 2-D planar NIR imaging techniques;(2) Develop 3-D optical tomography or angiography methods for evaluating lymph architecture and function in major lymphatic trunks using novel imaging agents;and (3) Demonstrate the use of new NIR lymphatic imaging agents for 3-D optical lymph angiography in humans. If successful, we will be able to demonstrate functional and architectural imaging in symptomatic and familial asymptomatic Milroy's and lymphedema distichiasis patients who are molecularly diagnosed through genotyping. The ability to image lymphatic function will enable us to understand the role of the lymphatics in health and disease.

Public Health Relevance

Malfunctioning lymphatics and lymphatic function are implicated in many diseases of increasing prevalence. Yet Milroy's and Lymphedema distichiasis are rare, congenital forms of lymphedema which provide a window to understand lymph dysfunction. In this work, we develop an approach to image for the first time, dynamic lymph function and architecture in these patients using novel near-infrared contrast agents employed in microdose administration for optical imaging.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-P (50))
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Tolunay, Eser
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University of Texas Health Science Center Houston
Schools of Medicine
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Rasmussen, John C; Zvavanjanja, Rodrick C; Aldrich, Melissa B et al. (2017) Near-infrared fluorescence lymphatic imaging of Klippel-Trénaunay syndrome. J Vasc Surg Venous Lymphat Disord 5:533-537
O'Donnell Jr, Thomas F; Rasmussen, John C; Sevick-Muraca, Eva M (2017) New diagnostic modalities in the evaluation of lymphedema. J Vasc Surg Venous Lymphat Disord 5:261-273
Aldrich, Melissa B; Velasquez, Fred C; Kwon, Sunkuk et al. (2017) Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis. Arthritis Res Ther 19:116
Greives, Matthew R; Aldrich, Melissa B; Sevick-Muraca, Eva M et al. (2017) Near-Infrared Fluorescence Lymphatic Imaging of a Toddler With Congenital Lymphedema. Pediatrics 139:
Wang, Xuejuan; Aldrich, Melissa B; Yang, Zhi et al. (2016) Influence of chelator and near-infrared dye labeling on biocharacteristics of dual-labeled trastuzumab-based imaging agents. Chin J Cancer Res 28:362-9
Rasmussen, John C; Aldrich, Melissa B; Tan, I-Chih et al. (2016) Lymphatic transport in patients with chronic venous insufficiency and venous leg ulcers following sequential pneumatic compression. J Vasc Surg Venous Lymphat Disord 4:9-17
Gonzalez-Garay, M L; Aldrich, M B; Rasmussen, J C et al. (2016) A novel mutation in CELSR1 is associated with hereditary lymphedema. Vasc Cell 8:1
Rasmussen, John C; Fife, Caroline E; Sevick-Muraca, Eva M (2015) Near-Infrared Fluorescence Lymphatic Imaging in Lymphangiomatosis. Lymphat Res Biol 13:195-201
Rasmussen, John C; Aldrich, Melissa B; Guilliod, Renie et al. (2015) Near-infrared fluorescence lymphatic imaging in a patient treated for venous occlusion. J Vasc Surg Cases 1:201-204
Agollah, Germaine D; Gonzalez-Garay, Manuel L; Rasmussen, John C et al. (2014) Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. PLoS One 9:e112548

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