Research
Our research is focused in four areas of basic and applied vascular biology and developmental biology:
1. The roles of PECAM-1 (CD31) in vasculogenesis and angiogenesis: Adhesion, scaffolding & signaling functions.
2. The inter-relationships between adhesion molecules (VLA-4 and PECAM-1) and Matrix Metalloproteinases in experimental autoimmune encephalomyelitis and vasculo- & angio-genesis.
3. Neuronal-glial-endothelial cell interactions ("the neuro-vascular niche") in gestational and post-natal neurovascular development. Mechanisms of vascular sympathetic innvervation. Implications in the development of neurodevelopmental handicaps in the premature infant population and dysregulation of vascular tone.
4. Maternal diabetes: Consequences for the fetus (Vitelline and embryonic vasculopathy and endocardial cushion defects).
Endothelial cells play central roles in the development, growth and maintenance of the vascular system as well as in the processes of inflammation, repair and metastasis. Vascular cell homotypic and heterotypic interactions and vascular cell interactions with the surrounding matrix, soluble factors and circulating blood cells (leukocytes, monocytes and lymphocytes), in part, direct the vascular cells' responses; yet much is still unknown about these complex interactions and the mechanisms involved in information transduction from the extracellular environment to the cell nucleus.
Specific projects in the laboratory currently include:
1) Elucidation of the roles of the cytoplasmic domains of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) in modulating endothelial and T cell behavior and vascular development as well as the signaling mechanisms involved. We are investigating how differential tyrosine and serine phosphorylation and alternative splicing of the PECAM-1 cytoplasmic domain modulates associations with specific proteins including beta- and gamma-catenin; STAT3 & 5, c-src, SHP-1 & 2 and small G proteins.
2) Identification and elucidation of the signal transduction pathways activated following T cell alpha4beta1 integrin-endothelial cell VCAM-1 binding and T cell PECAM-1 signaling prior to, during and following T cell transmigration into tissues. We are investigating the mechanisms of induction, clustering and activation of T cell and endothelial cell matrix metalloproteinase-2 [MMP-2 ], membrane type matrix metalloproteinase [MT1-MMP/MMP-14], matrix metalloproteinases [MMP-9] and CD44. Several knock out mouse strains (MMP-2 KO, MMP-9 KO, MMP-14 and CD31 KO) are also utilized in animal models of autoimmune encephalomyelitis.
3) Elucidation of the mechanisms of hypoxia-driven cerebral angiogenic responses noted in the premature infant population and their association with neurodevelopmental handicaps. Animal, organ and tissue culture models of chronic hypoxia coupled with cDNA array analyses are used to investigate the responses of the cerebral microvascular endothelial cells and neural stem cells to chronic sublethal hypoxia and the roles of the vasculature in the recovery process. We are also exploring the dynamic interactions of neural stem cells with endothelial cells in the formation, maintenance and remodeling of the neurovascular niches - neurogenic zones responsible for recovery following injury. We are also investigating the mechanisms of vascular sympathetic innervation, specifically the attractive and repulsive signaling molecules involved in modulating differential sympathetic innervation of specific vessels.
4) Elucidation of the mechanisms of the hyperglycemia-driven vasculopathy in the vitelline and embryonic circulations, and hyperglycemia-induced arrest of endocardial cushion (precursor cardiac valves) formation in murine conceptuses; abnormalities that are occur at increased frequency in the pregnancies of human maternal diabetes. Cultures of whole murine conceptuses and endocardial cushions are utilized along with confocal immunofluorescence microscopy, immunoprecipitation, immunoblotting techniques and proteomic analyses. Specifically, we are investigating the roles of a wide range of growth factors, transcription factors, structural proteins, enzymes and adhesion molecules identified by protein profiling in the process of epithelial to mesenchymal transformation (EMT) in the endocardial cushions of the developing heart. Our goals are to develop a protein chip for early diagnosis of fetuses at risk for developing cardiovascular abnormalities associated with maternal diabetes and to elucidate the underlying mechanisms as play during EMT in the endocardial cushions.
Individuals working in my laboratory are exposed to a wide variety of biochemical, cell biological, molecular biological and developmental biological and tissue and organ culture techniques as well as several animal models utilizing transgenic and knock-out technologies
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People
Current members of the Madri laboratory:
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Yue Wu, MD, PhD, Associate Research Scientist. Yue is working on elucidating the roles of PECAM-1 (CD31) in bone metabolism, specifically investigating its roles in modulating crosstalk between hematopoiesis and bone cells. She is also investigating PECAM-1's roles in modulating the immune response, specifically, its role in lymphangiogenesis.
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Qi Li, PhD, Associate Research Scientist. Qi is working on elucidating the dynamic crosstalk between endothelial cells and neural stem cells in the subventricular neurovascular niche and their responsiveness to the chronic sublethal hypoxic insult experienced by many prematurely-born infants.
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Sujata Kar, PhD, Associate Research Scientist. Sujata is investigating the roles of selected immune cell surface molecules (CD44 and MMP-14) and matrix metalloproteinases (MMP-2 and MMP-9) in the process of transendothelial migration in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis.
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Anjali Nath, PhD, Postdoctoral Fellow. Anjali has demonstrated the effectiveness of a protein profiling approach in the identification of novel proteins involved in epithelial to mesenchymal transformation in the cardiac cushions during heart development and is elucidating the signaling pathways that a selected number of these proteins play roles in. She is also developing a protein chip that may be useful in aiding in the early diagnosis of fetal cardiovascular anomalies frequently observed in the offspring of diabetic mothers.
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Jennifer Long, Graduate Student, Cellular & Molecular Physiology. Jennifer is investigating the molecular mechanisms of vascular sympathetic innervation. Specifically she is identifying attractive and repulsive signaling molecules differentially expressed by innervated and non-innervated vessels using traditional cell biological and pharmacological methods and suppressive hybridization techniques to identify novels signaling molecules involved in this process. The importance of understanding and controlling sympathetic innervation in specific vascular beds is thought to be important and may have important clinical implications in a variety of clinical settings including its disruption following heart transplantation.
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Jaime Liu, PhD, Visiting Scientist, China. Jaime will arrive in late Nov., 2007.
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Sandra Canosa, Associate in Research II. Sandra is investigating the role of PECAM-1 signaling as a modulator of metalloproteinase induction in endothelial cells and its role as a co-stimulatory molecule in T cells. Sandy also participates in Anjali's, Sugata's and Jennifer's projects
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Michael Michaud, MS, Associate in Research II. Michael is involved in maintaining our mouse colony, specifically setting up specific matings and genotyping, phenotyping and characterizing the behaviors of the various knock out and transgenic mice. He also participates in Qi's, Anjali's, Sugata's and Jennifer's projects. |
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Publications
Recent Publications:
Wu, Y., Welte, T., Michaud, M., Jiang, X., Madri, J.A., PECAM-1: A multifaceted regulator of megakaryocytopoiesis, Blood, 110(3):851-859, 2007.
Zhang, J., Biswas, P, Li, P., Kelm, R., Kashgarian, M., Madri, J.A., PECAM-1 Modulates Thrombin-Induced Tissue Factor Expression on Endothelial Cells, J. Cell. Physiol., 210(2):527–537, 2007.
Li, Q., Ford, M., Lavik, E., Madri, J.A., Modeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells - an in vitro study, J. Neurosci., 84(8):1656-68, 2006.
Biswas, P., Canosa, S., Schoenfeld, D.S., Schoenfeld, J., Li, P., Cheas, L.C., Zhang, J., Cordova, A., Sumpio, B.E., and Madri, J.A., PECAM-1 Affects GSK-3beta-mediated b-catenin Phosphorylation and Degradation. Amer. J. Pathol., 169 (1):314-324, 2006.
Wu, Y., Stabach, P., Michaud, M., Madri, J.A., Neutrophils Lacking PECAM-1 Exhibit Loss of Directionality in IL8-Induced Chemotaxis, J. Immunol.,175:3484-3491, 2005.
Carrithers, M., Tandon, S., Canosa, S., Michaud, M., Graesser, D. and Madri, J.A., Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice, Amer. J. Pathol., 166: 185-196, 2005.
Esparza, J., Kruse, M., Lee, J., Michaud, M and Madri, J.A., MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. FASEB J. 18: 1682-1691, 2004.
Recent Reviews:
Madri, J.A., Graesser, D., Cell Migration in the Immune System: The Evolving Inter-related Roles of Adhesion Molecules and Proteinases. Develop. Immunol., 7: 103-116, 2000.
Ilan, N., Madri J.A., PECAM-1: Old friend, new partners, Curr. Opin. in Cell Biol., 15(5):515-24, 2003.
Madri, J.A., Enciso, J., Pinter, E., Maternal diabetes: Effects on embryonic vascular development – A VEGF-A mediated process., Ped. Develop. Pathol., 6(4):334-341,.2003.
Nath A.K., Madri J.A., The Roles of Nitric Oxide in Murine Cardiovascular Development, Develop. Biol., 292(1):25-33, 2006.
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