Stone Lab

Overview

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.

Research Projects

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.

Group Members

Meet our research team:

• James R. Stone, MD, PhD
  Associate Professor of Pathology, Harvard Medical School
  Head of Cardiovascular Pathology and Director of Autopsy Pathology, Massachusetts General Hospital
• Mikhail Panchenko, PhD, Research Scientist

Publications

An elevated IgG4 response in chronic infectious aortitis is associated with aortic atherosclerosis.Siddiquee Z, Smith RN, Stone JR. Mod Pathol. 2015 Nov;28(11):1428-34.

Optimization of Serum Immunoglobulin Free Light Chain Analysis for Subclassification of Cardiac Amyloidosis. Halushka MK, Eng G, Collins AB, Judge DP, Semigran MJ, Stone JR. J Cardiovasc Transl Res. 2015 Jun;8(4):264-8.

Altered vascular activation due to deficiency of the NADPH oxidase component p22phox. Wang H, Albadawi H, Siddiquee Z, Stone JM, Panchenko MP, Watkins MT, Stone JR. Cardiovasc Pathol. 2014 Jan-Feb;23(1):35-42.

Giant cell aortitis of the ascending aorta without signs or symptoms of systemic vasculitis is associated with elevated risk of distal aortic events.

Wang H, Smith RN, Spooner AE, Isselbacher EM, Cambria RP, MacGillivray TE, Stone JH, Stone JR. Arthritis Rheum. 2012 Jan;64(1):317-9.

Protein kinase CK1alphaLS promotes vascular cell proliferation and intimal hyperplasia. Panchenko MP, Siddiquee Z, Dombkowski DM, Alekseyev YO, Lenburg ME, Walker JD, Macgillivray TE, Preffer FI, Stone JR. Am J Pathol. 2010 Sep;177(3):1562-72.

Up-regulation of a hydrogen peroxide-responsive pre-mRNA binding protein in atherosclerosis and intimal hyperplasia. Panchenko MP, Silva N, Stone JR. Cardiovasc Pathol. 2009 May-Jun;18(3):167-72.