The broad goal of this project is to define the molecular anatomy of the vasculature in multiple organs and to provide distinct molecular signatures unique to each vasculature. Considerable molecular diversity exists at the microvascular endothelial cell surface among organs, including the expression of organ-specific proteins which can provide key basic data necessary to investigate the mechanisms underlying the unique expression patterns as well as organ-specific vascular targets that can be used for site-specific drug delivery and molecular imaging. Defining the vascular proteome, discovering organ-specific targets, and developing suitable organ-specific probes are the goals of this project.
The specific aims of this project are: i) To combine novel subfractionation and mass spectrometry techniques to map the accessible vascular proteome of normal major organs and, through comparative analysis, uncover tissue-modulated and possibly organ-induced vascular proteins;ii) To generate and characterize antibodies specific for organ-induced vascular proteins as a means of determining the degree of molecular diversity of endothelia, performing detailed expression profiling, and creating potential tissue-targeting probes;and iii) To validate the utility of any apparent organ-specific targets and their antibodies by assessing organ-specific delivery and endothelial cell processing in vivo. In this proposal, we combine hypothesis-driven investigation with global analytical tools to establish better the validity of the hypothesis of tissue-modulated endothelial cell diversity in vivo. We use in silico subtractive and bioinformatic filters to reduce data complexity by orders of magnitude to focus on a manageable subset of proteins appearing to be both tissue-modulated and IV-accessible. Target-specific antibodies will validate IV-accessible endothelial cell surface targets via tissue expression profiling and whole body SPECT imaging in vivo. Intravital microscopy will be used to visualize endothelial cell processing of targeting antibodies in vivo. Such basic, molecular information is critical for establishing vascular function and is required for research in vascular biology, pharmacology, physiology, and development. This project is likely to provide clinically important targets potentially useful for organ-specific drug and gene delivery in vivo.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Chrastina, Adrian; Pokreisz, Peter; Schnitzer, Jan E (2014) Experimental model of transthoracic, vascular-targeted, photodynamically induced myocardial infarction. Am J Physiol Heart Circ Physiol 306:H270-8
Chrastina, Adrian; Schnitzer, Jan E (2012) Laser-targeted photosensitizer-induced lung injury: noninvasive rat model of pulmonary infarction. Exp Lung Res 38:1-8
Griffin, Noelle M; Schnitzer, Jan E (2011) Overcoming key technological challenges in using mass spectrometry for mapping cell surfaces in tissues. Mol Cell Proteomics 10:R110.000935
Chrastina, Adrian; Massey, Kerri A; Schnitzer, Jan E (2011) Overcoming in vivo barriers to targeted nanodelivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:421-37
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Chrastina, A; Valadon, P; Massey, K A et al. (2010) Lung vascular targeting using antibody to aminopeptidase P: CT-SPECT imaging, biodistribution and pharmacokinetic analysis. J Vasc Res 47:531-43
Griffin, Noelle M; Yu, Jingyi; Long, Fred et al. (2010) Label-free, normalized quantification of complex mass spectrometry data for proteomic analysis. Nat Biotechnol 28:83-9
Massey, Kerri A; Schnitzer, Jan E (2009) Targeting and imaging signature caveolar molecules in lungs. Proc Am Thorac Soc 6:419-30
Testa, Jacqueline E; Chrastina, Adrian; Li, Yan et al. (2009) Ubiquitous yet distinct expression of podocalyxin on vascular surfaces in normal and tumor tissues in the rat. J Vasc Res 46:311-24
Li, Yan; Yu, Jingyi; Wang, Yipeng et al. (2009) Enhancing identifications of lipid-embedded proteins by mass spectrometry for improved mapping of endothelial plasma membranes in vivo. Mol Cell Proteomics 8:1219-35

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