Joseph Anthony Madri MD, PhD
Professor of Pathology; Director of Education
Connective tissue disorders; Cell-Matrix and Cell-Cell Interactions; Integrin-Mediated Signaling; Cardio-vascular development; Angiogenesis and Vascular Biology; inflammation; T-cell-Endothelial cell interactions
Current Projects1) Elucidation of the mechanisms underlying the increased incidence of congenital abnormalities (cardiovascular) in the offspring of maternal diabetics and the development of diagnostic methods to enable earlier diagnosis.
2) 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 transmigrtation through endothelial cells during inflammation.
4) Elucidation of the roles of PECAM-1 (CD31) in vasculo- and angio-genesis, permeability, inflammation, directed migration, hemostasis and hematopoiesis and bone metabolism.
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), integrins (selected beta1, beta 2 and beta 3 integrins), junction associated molecules and extracellular matrix components 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) 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.
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 analysis are used to investigate the responses of the cerebral microvascular endothelial cells and the roles of the vasculature in causing resultant neurodevelopmental handicaps.
4) Elucidation of the mechanisms of the hyperglycemia-driven vasculopathy in the vitilline and embryonic circulations of murine conceptuses noted in maternal diabetes. Cultures of whole murine conceptuses and endocardial cushions are utilized along with confocal immunofluorescence microscopy, immunoprecipitation and immunoblotting techniques. Specifically, we are investigating the roles of VEGF and VEGF receptors, PECAM-1 (CD31) and matrix metalloproteinases in this hyperglycemia-induced vasculopathy.