Skin Diseases Research Center, Yale
Stem Cell Center, Yale: Stem Cell Niche and Homing
Endothelial cells play central roles in development and maintenance of the vascular system and in the processes of inflammation and metastasis. Interactions with cell adhesion molecules, surrounding matrix, and soluble factors directs endothelial cell responses; yet little is known about these complex interactions and the mechanisms involved in signal transduction. Specifically, we are investigating the roles of homotypic and heterotypic cell adhesion molecules, integrins, junction associated molecules, and extracellular matrix components in modulating vascular development and behavior. We are also investigating neural stem cell-endothelial cell interactions and the roles of T-cell and endothelial cell proteinases and proteinase inhibitors in modulating T-cell transendothelial migration and their roles in initiating and maintaining the inflammatory response in murine models of autoimmune disease and in several tissue culture models. A multi-disciplinary approach is used which includes the use of knockouts, transgenics, tissue and embryo culture model systems of cell adhesion, migration, and angiogenesis.
Extensive Research Description
Research Focus: The interests of my laboratory center around investigations of signaling pathways stimulated following endothelial cell-cell and endothelial cell-extracellular interactions and how they influence the processes of Vasculogenesis, angiogenesis and transendothelial migration.
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 little is known about these complex interactions and the mechanisms involved in information transduction from the extracellular environment to the cell nucleus.
We are currently investigating the roles of selected homotypic and heterotypic cell adhesion molecules (PECAM-1 & CD44), integrins (selected beta1, beta 2 and beta 3 integrins), junction associated molecules (VE-cadherin, ZO-1, Occludin) and extracellular matrix components (MMPs) in modulating vascular cell and T cell behavior (attachment, spreading, proliferation, migration, interactions with mononuclear (T) cells and angiogenesis). 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) and CD44 in modulating endothelial and T cell behavior, vascular development and dermal wound healing as well as the signaling mechanisms involved. We are investigating how differential tyrosine and serine phosphorylation of the PECAM-1 cytoplasmic domain modulates associations with specific proteins including beta- and gamma-catenin; STAT3&5, c-src, SHP-2 and small G proteins. We are also investigating the dynamic interactions between CD44 and CD31.
2) Identification and elucidation of the signal transduction pathways activated following T cell-endothelial cell binding and subsequent CD44 and 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. Selected knock out mouse strains (CD44 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 analysis are used to investigate the responses of the cerebral microvascular endothelial cells and the roles of the vasculature in causing resultant neurodevelopmental handicaps. The dynamic roles of HIF-1alpha and Sox10 in endothelial and neural stem cell responses to and recovery from hypoxic insult are being investigated.
1) Elucidation of the mechanisms involved in the recovery of neurodevelopmental handicaps incurred during and following premature birth and recovery from spinal cord injury.
3) Elucidation of the mechanisms involved in lymphocyte transmigration through endothelial cells during inflammation.
4) Elucidation of the roles of PECAM-1 (CD31) and CD44 in vasculo- and angiogenesis, permeability, inflammation, directed migration, hemostasis and hematopoiesis and bone metabolism.
- Li, Q, Canosa S, Michaud, M., Flynn, K., Krauthammer, M., J.A. Madri. Modeling the Neurovascular Niche: Unbiased Transcriptome Analysis of the Murine Subventricular Zone in Response to Hypoxic Insult, PLOS One, In Press, 2013.
- Flynn, K., Michaud, M., J.A. Madri. CD44 Deficiency Contributes to Enhanced Experimental Autoimmune Encephalomyelitis: A Role in Immune Cells and Vascular Cells 2 of the Blood Brain Barrier3, American Journal of Pathology, 182(4):1322-1336, 2013.
- Flynn, K., Michaud, M., Canosa, S., J.A. Madri. CD44 Regulates Vascular Endothelial Barrier Integrity via a PECAM-1 Dependent Mechanism, Angiogenesis, 16:689-705, 2013.
- Williams, C., Rauch, M.F., Michaud, M., Robinson, R., Madri J., Lavik, E., Neural Progenitor Cells Control in vivo Formation of Engineered Functional Vascular Networks, PLOS One, 2012;7(12):e53208. doi: 10.1371/journal.pone.0053208. Epub 2012 Dec 27.
- Wu, Y., Welte, T., Michaud, M., Jiang, X., Madri, J.A., PECAM-1: A multifaceted regulator of megakaryocytopoiesis, Blood, 110(3):851-859, 2007.
- Ford, M.C., Bertram, J.P., Hynes, S.R., Michaud, M., Li, Q., Young, M., Segal, S.S., Madri, J.A., Lavik, E.B., A novel macroporous hydrogel for the culture of neural progenitor and endothelial cells to form functional vascular networks in vivo, Proc. Natl. Acad. Sci. (USA), 103 (8):2512-2517, 2006.
- Li, Q., Michaud, M., Stewart, W., Schwartz, M, Madri, J.A., Modeling the Neurovascular Niche: Murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn, J. Neurosci., 86(6):1227-1242, 2008.