We and our collaborators have shown that cells undergoing stress (viral, endoplasmic reticulum, or hyperglycemic) or injury (wounds) synthesize/deposit an abnormal hyaluronan (HA)-based matrix with structural information that inflammatory cells recognize. We aim to determine: underlying cellular mechanisms that initiate matrix synthesis; internal matrix structures differing from normal HA matrices; and mechanisms whereby inflammatory cells (mast cells, eosinophils, neutrophils, monocytes/macrophages) adhere to and degrade abnormal HA matrix all key responses in regulation/progression of inflammatory processes.
With our 2011 NIH "Program of Excellence in Glycosciences" award, we study HA matrix and its interactions with leukocytes in vasculopathies in diabetes, wound healing, inflammatory bowel disease, pulmonary hypertension, and glycocalyx/pericellular matrix modification in vascular development.
We also participate on an NIH-funded project on asthma (S. Erzurum, M.D., PI) using murine airway myofibroblast cultures and a novel organotypic airway epithelium model to determine cellular responses to poly I:C (a viral mimetic) and tunicamycin (endoplasmic reticulum stressor). These two stimuli induce abnormal HA matrices differently. Primary murine mast cells interact with this matrix in early responses to external stresses in lung. Our collaborations continue with M. Aronica, M.D., on the matrixs role in transgenic mice (TSG-6-null/CD-44-null mice) in the ova/ova challenge asthmatic model; A. Wang on the effect of hyperglycemia in producing this matrix in kidney and bone of streptozotocin-treated diabetic rats; and E. Maytin, M.D., Ph.D., and J. Mack, Ph.D., on how this matrix affects wound healing.
We work to discover how a very large sugar molecule (hyaluronan) interacts with cells that are exposed to viruses, conditions of glucose (sugar) overload, or actual wounds to form an abnormal "matrix" around themselves that attracts certain cells that respond that respond when parts of the body become infected or inflamed. We hope to find what makes the matrix form, how it differs from normal matrix, and how the cells that respond to infection/inflammation get to and interact with the abnormal matrix. With a 2011 NIH Program Project Grant award and other funding, we are studying how the hyaluronan matrix works in the setting of diabetes, wound healing, inflammatory bowel disease, certain cancers, and the lung diseases asthma and pulmonary hypertension.
Aronica, Mark, M.D., Depts. of Pulmonary, Allergy and Critical Care Medicine and Pathobiology, Cleveland Clinic
de la Motte, Carol, Ph.D., Dept. of Pathobiology, Cleveland Clinic
Dweik, Raed, M.D., Depts. of Pulmonary, Allergy and Critical Care Medicine and Pathobiology, Cleveland Clinic
Erzurum, Serpil, M.D., Chair, Dept. of Pathobiology, Cleveland Clinic
Ghatak, Shibnath, Ph.D., Dept. of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC
Glant, Tibor T., M.D., Depts. of Orthopedic Surgery, Biochemistry, and Internal Medicine, Rush University Medical Center, Chicago, Illinois
Li, Xiaoxia, Ph.D., Dept. of Immunology, Cleveland Clinic
Mack, Judith, Ph.D., Dept. of Biomedical Engineering, Cleveland Clinic
Majors, Alana, Ph.D., Dept. of Pathobiology, Cleveland Clinic
Maytin, Edward, Ph.D., M.D., Depts. of Biomedical Engineering and Dermatology, Cleveland Clinic
Misra, Suniti, Ph.D., Dept. of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC
Muschler, George, M.D., Depts. of Biomedical Engineering and Orthopaedic
Surgery, Cleveland Clinic
Passi, Alberto, Ph.D., Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Varese, Italy
Tammi, Markku I., M.D., Dept. of Biomedicine, Univ. of Kuopio, Kuopio,
Tammi, Raija H., M.D., Dept. of Biomedicine, Univ. of Kuopio, Kuopio,
Mack JA, Feldman RJ, Itano N, Kimata K, Lauer M, Hascall VC, Maytin EV. Enhanced Inflammation and Accelerated Wound Closure Following Tetraphorbol Ester Application or Full-Thickness Wounding in Mice Lacking Hyaluronan Synthases Has1 and Has3. J Invest Dermatol. 2011 Aug 18. doi: 10.1038/jid.2011.248. [Epub ahead of print]
Wang A, de la Motte C, Lauer M, Hascall V. Hyaluronan matrices in pathobiological processes. FEBS J. 2011;278:1412-8. doi: 10.1111/j.1742-4658.2011.08069.x.
Ren J, Hascall VC, Wang A. Cyclin D3 mediates synthesis of a hyaluronan matrix that is adhesive for monocytes in mesangial cells stimulated to divide in hyperglycemic medium. J Biol Chem. 2009;284:16621-32.
Misra S, Hascall VC, De Giovanni C, Markwald RR, Ghatak S. Delivery of CD44 shRNA/nanoparticles within cancer cells: perturbation of hyaluronan/CD44v6 interactions and reduction in adenoma growth in Apc Min/+ MICE. J Biol Chem. 2009;284:12432-46.
Lerner Research Institute
Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195