My laboratory is interested in investigating the biological effects of mechanical forces on the cells with emphasis on the interplay between cellular mechanics and gene programs for growth, differentiation, extracellular matrix synthesis and degradation and apopotosis. We are particularly interested in understanding how cells from various tissue beds (e.g., bladder, vasculature) convert mechanical signals into a biological response and how abnormal responses of the cells to mechanical stimuli induce alterations of cellular phenotype and function and lead to organ system failure. We are using several models of mechano-sensitive genes such as those encoding the CCN growth factors Cyr61/CCN1 and CTGF/CCN2, extracellular matrix proteins such as collagen and elastin and growth factors such as IGF-I and VEGF, to study the mechanotransduction process and the role of mechanical signals in pathological conditions. Our approaches integrate in vitro studies with in vivo animal studies to ascertain the in vivo relevance of the mechanistic studies carried out in vitro.
The CCN proteins are also emerging as key modulators of both angiogenesis and fibrosis which are essential components in development, growth, wound healing and regeneration. These processes commonly occur together in many disease states in which neovascularization initiates the pathological cascade such as that in diabetic nephropathy, cardiomyopathy, uropathy and retinopathy. Interestingly, the biological activities of the CCN proteins are both tissue- and stimulus-dependent. In the myocardium, the CCN proteins help drive sprouting of new vessels to improve myocardial perfusion to meet increased oxygen demands after ischemic injury while in the retinal microvasculature, they initiate program cell death under hyperglycemic conditions. We are interested in deciphering the molecular mechanisms whereby these proteins achieve these pleitropic acitivities and the regulatory mechanisms involved. We are using a wide variety of biochemical and molecular biological approaches including genome-wide profiling microarrays and transgenic animals to tease out the proper effects of these proteins in reprogramming both gene expression and cellular phenotype. These research studies have clinical implications in the control of tissue remodeling associated with obstructive and cardiovascular diseases and diabetes.
Funded by Grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation.
SELECTED RECENT PUBLICATIONS
Liu H, Yang R, Chowdhury A, Tinner B, Schutze N and Chaqour B. Cysteine-rich protein 61 and connective tissue growth factor induce de-adhesion and anoikis of retinal pericytes. Endocrinology, (In Press) 2008.
Lee H.Y., Chung, J.W., Youn, S.W., Kim, J.Y., Park, K.W., Koo, B.K., Oh, B.H., Park B., Chaqour B, Walsh K, Kim HS. Forkhead transcription factor FOXO3a is a negative regulator of angiogenic immediate early gene CYR61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ. Res. 100(3):372-80, 2007.
Espinoza-Derout J., Wagner M., Shahmiri K., Mascareno E., Chaqour B, Siddiqui MA. Pivotal role of cardiac lineage protein-1 (CLP-1) in transcriptional elongation factor P-TEFb complex formation in cardiac hypertrophy. Cardiovasc Res, 75(1): 129-38, 2007.
Yang R., Liu H., Chaqour B. Matrix Metalloproteinase-2 (MMP-2) Expression and Apoptogenic Activity in Retinal Pericytes: Implications in Diabetic Retinopathy. An. N. Y. Acad. Sci. 1103: 196-201, 2007.
Chaqour, B. and Goppelt-Strueb, M. Mechanical Regulation and Function of the Cyr61/CCN1 and CTGF/CCN2 Proteins: Implications in Mechanical Stress-Associated Pathologies. Eur. J. Biochem., 273: 3639-3649, 2006.
Chaqour, B., Yang, R. and Sha, Q. Mechanical Stretch Regulates the Promoter Activity of the Profibrotic Factor CTGF/CCN2 through Increased Actin Polymerization and NF-?B Activation. J. Biol. Chem. 281(29): 20608-20622, 2006.
Zhou D., Herrick, D., Rosenbloom J. and Chaqour B. Cyr61 Regulates the Expression of VEGF, av Integrin Subunit and a-Actin Genes through Cytoskeletally-Based Mechanotransduction Mechanisms. J. Appl. Physiol. 98: 2344-2354, 2005.
Chaqour, B. and Goppelt-Strueb, M. Regulation of CCN proteins by alterations of the Cytoskeleton. In: CCN Proteins: A new Family of Cell Growth Regulators. Imperial College Press, World Scientific. London, UK. 14:70-119, 2005.
Ibrul Chowdhury and Brahim Chaqour. Regulation of Connective Tissue Growth Factor (CTGF/CCN2) Gene Transcription and mRNA Stability in Smooth Muscle Cells: Involvement of RhoA GTPase and Sensitivity to Actin Dynamics. Eur. J. Biochem. 271, 4436-4450, 2004.
Kim KH, Min YK, Baik JH, Lau LF, Chaqour B and Chung KC. Expression of angiogenic factor Cyr61 during neuronal cell death via the activation of c-Jun N-terminal kinase and serum response factor. J. Biol. Chem. 278: 16, 13847-13854, 2003.
Han JS, Macarak E, Rosenbloom J, Chung KC and Chaqour B. Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38 mitogen-activated protein kinase signaling pathways: Role of cyclic AMP-responsive element binding protein (CREB) and AP-1 transcription factors. Eur. J. Biochem. 270(16):3408-21, 2003.
Chaqour B, Han JS, Tamura I and Macarak EJ. Mechanical regulation of IGF-I and IGF-binding protein gene transcription in bladder smooth muscle cells. J. Cell. Biochem. 84: 264-277. 2002.
Chaqour B, Whitbeck C, Han JS, Macarak E, Horan P, Chichester P and Levin R. Cyr61 and CTGF are molecular markers of bladder wall remodeling after outlet obstruction. Am. J. Physiol. 283: E765-E774, 2002.
Chowdhury I, and Chaqour B. Modulation of Connective Tissue Growth Factor (CTGF/CCN2) Expression through Cytoskeletally-Based Transduction Mechanisms. 2004 (In Press)
Chaqour, B., Yang, R. and Sha, Q. Mechanical Stretch Regulates the Promoter Activity of the Profibrotic Factor CTGF/CCN2 through Increased Actin Polymerization and NF-kB Activation. J. Biol. Chem. 2006.
Chaqour, B. and Goppelt-Strueb, M. Regulation of CCN proteins by alterations of the Cytoskeleton. In: CCN Proteins: A new Family of Cell Growth Regulators. Imperial College Press, World Scientific. 14:4, 70-89, 2005.
Zhou D., Herrick, D., Rosenbloom J. and Chaqour B. Cyr61 Regulates the Expression of VEGF, av Integrin Subunit and a-Actin Genes through Cytoskeletally-Based Mechanotransduction Mechanisms. J. Appl. Physiol. 98: 2344-2354, 2005.
Chowdhury, I. and Chaqour, B. Regulation of Connective Tissue Growth Factor (CTGF/CCN2) Gene Transcription and mRNA Stability in Smooth Muscle Cells: Involvement of RhoA GTPase and Sensitivity to Actin Dynamics. Eur. J. Biochem. 271, 4436-4450, 2004.
Kim KH, Min YK, Baik JH, Lau LF, Chaqour B and Chung KC. Expression of angiogenic factor Cyr61 during neuronal cell death via the activation of c-Jun N-terminal kinase and serum response factor. J. Biol. Chem. 278: 16, 13847-13854, 2003.
Han JS, Macarak E, Rosenbloom J, Chung KC and Chaqour B. Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways: Role of cyclic AMP-responsive element binding protein (CREB) and AP-1 transcription factors. Eur. J. Biochem. 270(16):3408-21, 2003.
Meneveau NF, Klugherz BD, Chaqour B, Golden MA, Jouille MM, Macarek E, Weisz PB, Wilensky RL. Separate and combined effects of local and continuous intravenous administration of beta-cyclodextrin tetradecasulfate on intimal hyperplasia after angioplasty in porcine coronary arteries. J. Cardiovasc. Pharmacol. Ther. 8(1):53-60, 2003.
Chaqour B, Whitbeck C, Han JS, Macarak E, Horan P, Chichester P and Levin R. Cyr61 and CTGF are molecular markers of bladder wall remodeling after outlet obstruction. Am. J. Physiol.(Endocrinol Metabol) 283E765-E774, 2002.
Chaqour B, Han JS, Tamura I and Macarak EJ. Mechanical regulation of IGF-I and IGF-binding protein gene transription in bladder smooth muscle cells. J. Cell. Biochem. 84: 264-277. 2002.
Meneveau NF, Klugherz B, Chaqour B, Vibha A, Tomaszewski JE, Macarak EJ, Weisz P, and Wilensky RL. b-cyclodextrin tetrasulfate inhibits neointima formation following PTCA in porcine coronary arteries: Effects on coagulation, mural thrombus formation and cellular accumulation. Coron. Artery Dis. 13(3):189-97.2002.