Malfunctioning lymphatics and lymphatic function are strongly implicated in metastatic cancer, asthma, diabetes, and obesity. Yet despite the importance of the lymphatics in these diseases, diagnostic imaging approaches to non-invasively monitor lymph function are non-existent. Recently, we reported the ability to non-invasively and dynamically image lymph function in the intact swine as well as in humans using a non- specific near-infrared fluorophore, IC-Green, as well as a molecular stain of lymph endothelium that targets the lymph vascular endothelium receptor, LYVE-1. In addition, upon developing imaging agents that molecularly target "activated" lymph endothelium, we hypothesize that we can image lymphangiogenesis. Our results demonstrate the feasibility of monitoring lymph flow and its molecular markers for the diagnosis and management of lymph diseases in a population of patients who suffer from primary and secondary lymphedema. In this research application, we hypothesize that: near infrared (NIR) optical methods can be used to image lymph flow, function, and remodeling to provide diagnostics and information on response to therapy. Specifically, we seek to: (1) Refine imaging hardware and develop software methodologies for automated imaging and analysis of lymph function in preclinical and clinical imaging studies;(2) Develop, synthesize, and validate molecularly targeting imaging agents that are specific to LYVE-1, hyaluronidase, and alpha-9 integrins that are involved in the process of lymphedema and lymphangiogenesis;(3) Develop functional lymph imaging methodologies in an immunocompetent SKH-1 mouse model of acquired lymphedema in order to assess the temporal progression of lymphedema using trace amounts of non-specific IC-Green and IRDye800CW to assess lymphatic function, and then to use molecular imaging agents that target LYVE-1, hyaluronan degradation, and alpha-9, alpha-v integrins expressed on proliferating LEC and BEC proliferation to track the progression and response to therapy;and finally to (4) Conduct imaging on human subject volunteers to establish baseline lymph function imaging parameters as well as on lymphedema patients to assess alteration in lymph function imaging parameters with disease progression and response/non-response to conventional therapy. The proposed work utilizes new developmental instrumentation and imaging agents, established mouse models of lymphedema, and a clinical trial team to translate discoveries in lymph imaging to patients. Project Narrative: Malfunctioning lymphatics and lymphatic function are strongly implicated in metastatic cancer, asthma, diabetes, and obesity. Yet despite the importance of the lymphatics in these diseases, diagnostic imaging approaches to non-invasively monitor lymph function are non-existent. In this work we develop new imaging techniques to assess lymph function and molecular markers in lymph disease and health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128919-05
Application #
8308008
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Zhang, Yantian
Project Start
2008-09-16
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$322,344
Indirect Cost
$93,453
Name
University of Texas Health Science Center Houston
Department
None
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Sevick-Muraca, Eva M; King, Philip D (2014) Lymphatic vessel abnormalities arising from disorders of Ras signal transduction. Trends Cardiovasc Med 24:121-7
Sevick-Muraca, Eva M; Kwon, Sunkuk; Rasmussen, John C (2014) Emerging lymphatic imaging technologies for mouse and man. J Clin Invest 124:905-14
Kwon, Sunkuk; Agollah, Germaine D; Wu, Grace et al. (2014) Spatio-temporal changes of lymphatic contractility and drainage patterns following lymphadenectomy in mice. PLoS One 9:e106034
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
Burrows, Patricia E; Gonzalez-Garay, Manuel L; Rasmussen, John C et al. (2013) Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci U S A 110:8621-6
Robinson, Holly A; Kwon, SunKuk; Hall, Mary A et al. (2013) Non-invasive optical imaging of the lymphatic vasculature of a mouse. J Vis Exp :e4326
Lapinski, Philip E; Kwon, Sunkuk; Lubeck, Beth A et al. (2012) RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest 122:733-47
Rasmussen, John C; Kwon, Sunkuk; Sevick-Muraca, Eva M et al. (2012) The role of lymphatics in cancer as assessed by near-infrared fluorescence imaging. Ann Biomed Eng 40:408-21
Kwon, S; Davies-Venn, C; Sevick-Muraca, E M (2012) In vivo dynamic imaging of intestinal motions using diet-related autofluorescence. Neurogastroenterol Motil 24:494-7
Sevick-Muraca, E M (2012) Translation of near-infrared fluorescence imaging technologies: emerging clinical applications. Annu Rev Med 63:217-31

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