Connective Tissue Diseases; Education, Medical; Inflammation; Pathology; T-Lymphocytes; Cell-Matrix Junctions; Endothelial Cells
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.
Specialized Terms: Connective tissue disorders; Cell-Matrix and Cell-Cell Interactions; Integrin-Mediated Signaling; Cardio-vascular and neuro-vascular development; Angiogenesis and Vascular Biology; inflammation; T-cell–Endothelial cell interactions
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.
- Canosa S, Michaud, M., Flynn, K., Krauthammer, M., J.A. Madri. Modeling the se to Hypoxic Insult, PLOS One, PLoS ONE 8(10): e76265, 2013. doi:10.1371/journal.pone.0076265http://dx.plos.org/10.1371/journal.pone.0076265.
- Yamamoto K, Protack CD, Tsuneki M, Hall MR, Wong DJ, Lu DY, Assi R, Williams WT, Sadaghianloo N, Bai H, Miyata T, Madri JA, Dardik A., Am J Physiol Heart Circ Physiol. 2013, Dec;305(12):H1718-25. doi: 10.1152/ajpheart.00590.2013. Epub 2013 Oct 4. PMID: 24097429
- Chunsik Lee, Anguo Liu, Alba Miranda-Ribera, Sang Won Hyun, Erik P. Lillehoj, Alan S. Cross, Antonino Passaniti, Joseph A. Madri, and Simeon E. Goldblum, J. Biol. Chem., 2014, 289(13):9121-9135
- Tsuneki, M., Madri, J.A., CD44 regulation of endothelial cell proliferation and apoptosis via modulation of CD31 and VE-cadherin expression., J Biol Chem. 2014, 289(9):5357-5370. doi: 10.1074/jbc.M113.529313. Epub 2014 Jan 14.PMID: 24425872
- McCarthy TL, Yun Z, Madri JA, Centrella M., Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts., Gene. 2014,539:141–151. doi: 10.1016/j.gene.2014.01.011. Epub 2014 Jan 15., PMID: 24440782
- Michael R. Hall, Kota Yamamoto, Clinton D. Protack, Masayuki Tsuneki, Go Kuwahara, Roland Assi, Kirstyn Brownson, Hualong Bai, Joseph Madri, Alan Dardik, Temporal Regulation of Venous Extracellular Matrix Components during Arteriovenous Fistula Maturation, J Vasc Access. 2014 doi: 10.5301/jva.5000290.
- Tsuneki, M., Madri, J.A. Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior, Mol Cell Biol., 34(24):4485-99, 2014. doi: 10.1128/MCB.00671-14,
- Yamamoto, K., Protack, C.D., Kuwahara, G., Tsuneki, M., Hashimoto, T., Hall, M.R., Assi, R., Brownson K.E.,m Foster, T.R., Bai, H., Wang, M., Madri, J.A., Dardik, A., Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo, Physiol. Reports, 2015 Mar;3(3). pii: e12348. doi: 10.14814/phy2.12348. PMID: 25780089
- Tsuneki, M., Madri J.A., Saku T., Cell-extracellular interactions in oral tumorigenesis: the roles of podoplanin and CD44 and modulation of the Hippo pathway, Journal of Oral Biosciences, March, 57(2), DOI:10.1016, 2015.
- Tsuneki, M., Hardee, S., Michaud, M., Morotti, R, Lavik, E, Madri JA. A Hydrogel-Endothelial Cell implant Mimics Infantile Hemangioma:, Modulation by Survivin and the Hippo pathway, Laboratory Investigation, Jul;95(7):765-80. doi: 10.1038/labinvest.2015.61. Epub 2015 May 11., PMID: 25961170.
- LI, Q., Tsuneki, M, Krauthammer, M., Couture, R., Schwartz, M., Madri, J.A., Modulation of Sox10, HIF-1, Survivin and YAP by minocycline in the treatment of neurodevelopmental handicaps following hypoxic insult, Amer J. Pathol., Sep;185(9):2364-78. doi: 10.1016/j.ajpath.2015.05.016. Epub 2015 Jul 22. PMID: 26209807
- Tsuneki, M., Madri J.A., CD44 influences fibroblast behaviors via modulation of cell-cell and cell-matrix interactions, affecting Survivin and Hippo pathways, Journal of Cellular Physiology, Aug 6. doi: 10.1002/jcp.25123.
- Ronald A. Albright, Paul Stabach, Wenxiang Cao, Dillon Kavanagh, Isabelle Mullen, Alexander A. Braddock, Mariel S. Covo, Guangxiao Yang, [Alexion Personnel], Stephanie Thorn, Xiangning Wang, Alejandro Negrete, Albert J. Sinusas, Joseph Shiloach, George Zubal, Joseph A. Madri, Enrique M. De La Cruz, and Demetrios T. Braddock, Untargeted ENPP1 Enzyme Replacement Therapy Prevents Mortality and Sequelae of GACI, Nature, In Press, 2015.