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Research at Mass General
James R. Stone, MD, PhD
Associate Professor of Pathology, Harvard Medical SchoolHead of Cardiovascular Pathology and Director of Autopsy Pathology, Massachusetts General Hospital
Simches Research Building, Rm 8236 185 Cambridge Street, CPZNBoston, MA 02114Phone: 617-726-8303Fax: 617-643-3566Email: email@example.com
The Stone Laboratory studies mechanisms underlying human vascular diseases, such as atherosclerosis and vasculitis. Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. The laboratory is seeking to understand the molecular processes resulting in atherosclerosis in order to combat this pervasive disease. Atherosclerosis is characterized by the development of necrotic/lipid cores within the intima of arteries at particular sites in the circulation. These necrotic/lipid cores form in the setting of a pre-existing intimal hyperplasia, characterized by the proliferation of smooth muscle-like cells in the intima. The laboratory is investigating both the signal transduction mechanisms responsible for the formation of the preatherosclerotic intimal hyperplasia as well as the factors stimulating the formation of intimal necrotic/lipid cores.
Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane -bound NADPH oxidases. These low physiologic levels of hydrogen peroxide are mitogenic, stimulating vascular cell growth and proliferation. The mechanisms by which low endogenous levels of hydrogen peroxide stimulate cellular proliferation are currently poorly understood. The laboratory is using molecular approaches with cultured vascular cells and cultured human arteries to identify signal transduction pathways activated by low physiologic levels of hydrogen peroxide. One such novel pathway identified in the laboratory is the CK1aLS /hnRNP-C signaling pathway, which has been shown to mediate hydrogen peroxide-stimulated mitogenic signaling in vascular cells and to promote intimal hyperplasia in cultured human arteries.
Intimal hyperplasia, the precursor lesion for atherosclerosis, forms both in vessels that are prone to develop atherosclerosis and in vessels remarkably resistant to atherosclerosis. Intimal hyperplasia can be formed in vitro with human artery segments in culture. The laboratory is using novel human artery culture models combined with molecular analyses of diseased human arteries to identify, characterize, and functionally assess the vascular wall factors that promote the transition from intimal hyperplasia to human atherosclerosis.
Mikhail Panchenko, PhD Research Scientist
Stone Lab Website
The Laboratory ofJames R. Stone, MD, PhD
Specific projects in the laboratory include elucidation of the biochemical pathways by which low levels of hydrogen peroxide stimulate cell proliferation in the vessel wall, and determination of the vascular extracellular matrix alterations in humans that promote the development of atherosclerosis.
Bibliography of James R. Stone via PubMed
Siddiquee Z, Smith RN, Stone JR. An elevated IgG4 response in chronic infectious aortitis is associated with aortic atherosclerosis. Mod Pathol. 2015; 28:1428-1434.
Halushka MK, Eng G, Collins AB, Judge DP, Semigran MJ, Stone JR. Optimization of serum immunoglobulin free light chain analysis for subclassification of cardiac amyloidosis. J. Cardiovasc Translat Res. 2015; 8:264-268.
Wang H, Albadawi H, Siddiquee Z, Stone JM, Panchenko MP, Watkins MT, Stone JR. Altered vascular activation due to deficiency of the NADPH oxidase component p22phox. Cardiovasc. Pathol. 2014; 23:35-42.
Wang H, Smith RN, Spooner AE, Isselbacher EM, Cambria RP, MacGillivray TE, Stone JH, Stone JR. Giant cell aortitis of the ascending aorta without signs or symptoms of systemic vasculitis is associated with elevated risk of distal aortic events. Arthrit. Rheum. 2012; 64:317-319.
Panchenko MP, Siddiquee Z, Dombkowski DM, Alekseyev YO, Lenburg ME, Walker JD, MacGillivray TE, Preffer FI, Stone JR. Protein kinase CK1LS promotes vascular cell proliferation and intimal hyperplasia. Am. J. Pathol. 2010; 177:1562-1572.
Panchenko MP, Silva N, Stone JR. Upregulation of a hydrogen peroxide responsive pre-mRNA binding protein in atherosclerosis and intimal hyperplasia. Cardiovasc. Pathol. 2009; 18: 167-172.
Massachusetts General Hospital
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