Phillip J. Stone
Boston University School of Medicine
Silvio Conte Building, Office: K301
72 E. Concord Street
Boston, MA 02118
BS, Swarthmore College, PA
MS, University of Pennsylvania, PA
PhD, Temple University, PA
Elastin proteolysis and repair in human pathology
Elastin is a highly crosslinked connective tissue protein with rubber-like tensile properties. As such it plays a key structural role in the blood vessels, lung and other organs. Under normal conditions elastin has a very slow rate of turnover. Proteolysis of elastin is associated with pathologic conditions; for example, pulmonary emphysema. Our research mission is to measure and understand pathologic elastin degradation and its failure to repair appropriately. We are currently working on understanding the signal transduction pathways that signal the upregulation of the repair mechanism. Another project is evaluating the delivery of recombinant human tropoelastin to loci in tissues requiring repair of elastin. We have shown that a portion of this tropoelastin becomes crosslinked into proteolytically damaged elastin. The laboratory is also involved in clinical studies involving elastin degradation. We have developed a novel assay for the measurement of specific elastin and collagen breakdown products that are cleared into the urine. Increased levels of these markers are found in a number of inflammatory conditions such as emphysema, cystic fibrosis, scleroderma, liver cirrhosis, inflammatory bowel diseases and provide a biochemical index of disease activity. We are currently partnering with a company in Cambridge. to design and test elastase inhibitors for treatment of pulmonary emphysema.
- Trafficking of endogenous smooth muscle cell cholesterol: a role for serum amyloid A and interleukin-1β. Pessolano LG Jr, Sullivan CP, Seidl SE, Rich CB, Liscum L, Stone PJ, Sipe JD, Schreiber BM. Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2741-50. doi: 10.1161/ATVBAHA.112.300243. Epub 2012 Sep 20.
- Micropatterned cell sheets with defined cell and extracellular matrix orientation exhibit anisotropic mechanical properties. Isenberg BC, Backman DE, Kinahan ME, Jesudason R, Suki B, Stone PJ, Davis EC, Wong JY. J Biomech. 2012 Mar 15;45(5):756-61. doi: 10.1016/j.jbiomech.2011.11.015. Epub 2011 Dec 15.
- Transgenic expression of an altered angiotensin type I AT1 receptor resulting in marked modulation of vascular type I collagen. Yu J, Taylor L, Rich C, Toselli P, Stone P, Green D, Warburton R, Hill N, Goldstein R, Polgar P. J Cell Physiol. 2012 May;227(5):2013-21. doi: 10.1002/jcp.22929.
- The critical role of the cellular thiol homeostasis in cadmium perturbation of the lung extracellular matrix. Zhao Y, Chen L, Gao S, Toselli P, Stone P, Li W. Toxicology. 2010 Jan 12;267(1-3):60-9. doi: 10.1016/j.tox.2009.10.021. Epub 2009 Oct 29.
- A zipper network model of the failure mechanics of extracellular matrices. Ritter MC, Jesudason R, Majumdar A, Stamenovic D, Buczek-Thomas JA, Stone PJ, Nugent MA, Suki B. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1081-6. doi: 10.1073/pnas.0808414106. Epub 2009 Jan 14.
- A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema. Guarnieri F, Spencer JL, Lucey EC, Nugent MA, Stone PJ. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10661-6. doi: 10.1073/pnas.1001349107. Epub 2010 Jun 1.
- Spencer JL, Stone PJ, Nugent MA. New insights into the inhibition of human neutrophil elastase by heparin. Biochemistry 2006,45:9104-9120.
- DiCamillo S.J., Yang S, Panchenko M.V, Toselli PA, Naggar EF, Rich CB, Stone P.J, Nugent MA, Panchenko M.P. Neutrophil elastase initiated EGFR/MEK/ERK signaling counteracts the stabilizing effect of autocrine TGF-? on tropoelastin mRNA in lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2006;291:L232-43.
- Berk JL,Hatch CA, Morris SM, Stone PJ, Goldstein RH. Hypoxia suppresses elastin repair by rat lung fibroblasts. Am J Physiol Lung Cell Mol Physiol: 2005; 289: L931-6.
- Black LD, Brewer KK, Morris SM, Schreiber BM, Toselli P, Nugent MA, Suki B, Stone PJ. Effects of elastase on the mechanical and failure properties of engineered elastin-rich matrices. J Appl Physiol 2005; 98:1434-1441.
- Buczek-Thomas JA, Lucey EC, Stone PJ, Chu CL, Rich CB, Carreras I, Goldstein RH, Foster JA, Nugent MA. Elastase mediates the release of growth factors from lung in vivo. Am J Respir Cell Mol Biol. 2004; 31:344-350.
- Stone, PJ, Morris, SM, Griffin, S, Mithieux, S, Weiss, AS. Building elastin. Incorporation of recombinant human tropoelastin into extracellular matrices using non-elastogenic Rat-1 fibroblasts as a source for lysyl oxidase. Amer. J. Respir. Cell Mol. Biol. 2001;24:733-739.
- Gottlieb DJ, Stone PJ, Sparrow D, Gale, ME, Weiss ST, Snider GL, O’Connor GT. Urinary desmosine excretion in smokers with and without rapid decline of lung function: The Normative Aging Study. Am J Respir Crit Care Med, 1996; 154:1290-1295.