Dr. Varani received his undergraduate degree from St. John's University in Collegeville, Minnesota and his Ph.D. at the University of North Dakota in 1974. After Post-Doctoral work at the University of Connecticut, he came to the University of Michigan as an Assistant Professor in 1980. He was promoted to Associate Professor in 1985 and became a Full Professor in 1991.
Skin biology, Skin atrophy, Fibrosis, Extracellular matrix, Metalloproteinase, Epithelial cell differentiation
Research activities activities in our laboratory are focused on understanding the process by which human skin atrophy occurs. Its antithesis – fibrotic skin disease – is also a focus. Our laboratory has developed and utilized sophisticated human tissue models to study the process of extracellular matrix synthesis and breakdown. Understanding the cellular and molecular events that regulate connective tissue production is the key to understanding both atrophy and fibrosis. As part of this effort, studies are focused on regulation of fibroblast proliferation. Signaling pathways controlling growth, extracellular matrix production, elaboration of matrix metalloproteinases and their inhibitors are being investigated. There are a number of agents that can be used therapeutically to modulate connective tissue synthesis and breakdown. Many of these produce an irritant- dermatitis. We have utilized chemically-induced skin irritation as a tool to help understand mechanisms of inflammatory skin disease such as psoriasis, drug-induced skin eruptions, rosacea etc. Sophisticated human tissue models and skin transplant models are used for these studies. While inflammatory skin diseases are immunological / inflammatory in nature, the resident cells, especially the keratinocytes, are integral to pathophysiology. Our laboratory has an active program to investigate the role of the keratinocyte in skin inflammation. Regulation of cell growth and differentiation is critical to this process.
Understanding how epithelial cell growth and differentiation in the skin are regulated is, therefore, an important ongoing activity in the laboratory. Epithelial cells in the colon are similar to epithelial cells in the epidermis. Therefore, much of what we have learned about the regulation of epithelial cell growth in the skin can be applied to the colon. In the colon, growth control studies are helping us understand how adenomatous polyps arise and how polyp formation can be controlled. As in the skin, epithelial cell proliferation in the colon is intimately related to differentiation. As in the skin, extracellular Ca2+ is critical to induction of differentiation. It has been shown in the colon, that differentiation by Ca2+ requires the presence of a function extracellular calcium-sensing receptor (CaSR). When a functional CaSR is present, colonic epithelial cells react to Ca2+ in the colonic fluid by upregulating E-cadherin and forming close cell-cell adhesions. As part of this process, b-catenin is sequestered in the cell surface-cytoskeletal complex and is, then, unavailable to serve as a nuclear transcription enhancer for growth-promoting Wnt signaling. Studies in the colon involve cell culture and animal models. In addition, we have developed and are utilizing an organ culture model of human colon tissue to understand the process of growth and differentiation in this tissue. These studies have implications not only for colon cancer but also, potentially, for inflammatory bowel disease.
Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. H. Zhang, S. K. Ramakrishnan, D. Triner, B. Centofanti, D. Maitra, B. Győrffy,J. S. Sebolt-Leopold, M. K. Dame, J. Varani, D. E. Brenner, E. R. Fearon, M. B. Omary,Y. M. Shah, 2015. Sci. Signal. 8, ra98 (in press).
Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: Promotion of a more differentiated, less malignant and indolent phenotype.Singh N, Aslam MN, Varani J, Chakrabarty S. Mol Carcinog. 2015 Jul;54(7):543-53. doi: 10.1002/mc.22123. Epub 2013 Dec 17.PMID:26076051
Monoclonal antibodies specific for oncofetal antigen--immature laminin receptor protein: Effects on tumor growth and spread in two murine models. McClintock SD, Warner RL, Ali S, Chekuri A, Dame MK, Attili D, Knibbs RK, Aslam MN, Sinkule J, Morgan AC, Barsoum A, Smith LB, Beer DG, Johnson KJ, Varani J. Cancer Biol Ther. 2015;16(5):724-32. doi: 10.1080/15384047.2015.1026484.
Clinical, Histologic, and Molecular Analysis of Differences Between Erythematotelangiectatic Rosacea and Telangiectatic Photoaging.Helfrich YR, Maier LE, Cui Y, Fisher GJ, Chubb H, Fligiel S, Sachs D, Varani J, Voorhees J.JAMA Dermatol. 2015 Aug 1;151(8):825-36. doi: 10.1001/jamadermatol.2014.4728.PMID:25798811
Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture.Ward NL, Bhagathavula N, Johnston A, Dawes SM, Fu W, Lambert S, Dame MK, Warner RL, Gudjonsson JE, Varani J, Elder JT.J Invest Dermatol. 2015 Mar;135(3):910-3. doi: 10.1038/jid.2014.445. Epub 2014 Oct 13. No abstract available.PMID:25310408
Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived.Dame MK, Jiang Y, Appelman HD, Copley KD, McClintock SD, Aslam MN, Attili D, Elmunzer BJ, Brenner DE, Varani J, Turgeon DK.Lab Invest. 2014 Feb;94(2):222-34. doi: 10.1038/labinvest.2013.145. Epub 2013 Dec 23.PMID:24365748
Preservation of bone structure and function by Lithothamnion sp. derived minerals.Aslam MN, Bergin I, Jepsen K, Kreider JM, Graf KH, Naik M, Goldstein SA, Varani J.Biol Trace Elem Res. 2013 Dec;156(1-3):210-20. doi: 10.1007/s12011-013-9820-7. Epub 2013 Oct 6.PMID:24096551
Role of calcium sensing receptor (CaSR) in tumorigenesis.Singh N, Promkan M, Liu G, Varani J, Chakrabarty S.Best Pract Res Clin Endocrinol Metab. 2013 Jun;27(3):455-63. doi: 10.1016/j.beem.2013.04.001. Epub 2013 May 6. Review. PMID:23856272