Department of Cell Biology Faculty

Connective Tissue Remodeling in Development and Diseases

Research focus in the Chaqour lab is on the adaptive and maladaptive responses of cells and tissues to local and environmental stresses/injuries whether they are mechanical/physical in nature (e.g., tissue overdistension/stretch, hemodynamic or pressure overload and shear stress deformation) or chemical stresses imparted by hypoxia, hyperoxia and/or ischemia. These studies have direct clinical implications in congenital and acquired diseases of the nervous, urinary, cardiovascular and digestive systems as well as in tumorigenesis.

One aspect of the research work in our lab is to investigate how cells from various tissue beds convert mechanical signals into biological responses and how abnormal responses of tissues to mechanical overload induce alterations of cellular phenotype and function and lead to organ system failure. Mechanical overload elicits a series of structural and functional changes that culminate in hypertrophy, hyperplasia and various degrees of fibrosis, particularly in smooth muscle-rich tissues of hollow organs. During normal tissue development, growth, angiogenic and fibrotic factors are expressed in a coordinated manner to allow (i) differentiation and growth of tissue, (ii) formation of extracellular matrix which provides the mechanical scaffolding within which organs and tissues are assembled and (iii) vascularization to meet the metabolic demands and allow tissue perfusion. Conversely, abnormal mechanical signals causes dysregulation of these processes i.e., induce hypertrophic growth but an insufficient angiogenesis or induces fibrosis without associated cell growth. Consequently, tissue becomes dysfunctional due to ischemia and/or altered mechanical properties.

We have identified two mechano-sensitive genes, the cysteine-rich protein 61 (Cyr61/CCN1) and connective tissue growth factor (CTGF/CCN2) as  key modulators of cell and tissue responses to mechanical and chemical insults. Cyr61/CCN1 and CTGF/CCN2 belong to a group of matricellular proteins that appear in the extracellular matrix only at specific stages of development or in association with pathological conditions. CCN1 is required for proper angiogenesis and vasculogenesis during development by virtue of its ability to dictate angiogenic cell decisions about differentiation, migration, proliferation, survival, apoptosis and modulation of expression of key gene products including Wnt ligands, their receptors and their gene targets. Our studies are designed to determine the effects of CCN1-derived signals, or lack thereof, on tissue function during development and diseases of organ systems, the functional significance of CCN1 interaction with specific partners (shown in the diagram), and the relationship between CCN1 and other developmental pathways e.g., Notch and Wnt signaling pathways. The in vivo activities of CCN1 are compared to those of its structurally-related family member, CCN2/CTGF, although CTGF is, a priori, involved in the pathogenesis of fibrotic diseases and in skeletal development. Our investigative paradigm is based on the concept that fibrosis is a potentially reversible process and that inhibition of CTGF expression allows fibrosis resolution with remodeling and restitution of normal or near-normal tissue architecture.

Another research focus in the Chaqour lab is on the molecular bases of angiogenic cell function and behavior in physiological and pathological retinal angiogenesis. Specifically, this project investigates the ability of CCN1 to induce endothelial commitment of hematopoietic stem cells and to recruit accessory cells (e.g., pericytes, astrocytes) to vaso-obliterated sites and the relevance of CCN1-based gene and cell therapy in vascular regeneration and/or vessel normalization following hyperoxic and/or hypoxic stress in the retina. We also investigate the structure-to-function relationship of CCN1 and identify bioactive peptides derived form CCN1 or small molecule mimetics to control its expression and/or activities for therapeutic applications.  

We are using a wide variety of biochemical, molecular biological and immunohistological approaches including genome-wide profiling microarrays, transgenic and conditional knock-out animals, microRNA target identification  and genetic models of specific miRNA deficiency to tease out the proper effects of CCN1 and CCN2 in reprogramming both gene expression and cellular phenotypes.

Supported  by Grants from the National Institutes of Health.

SELECTED RECENT PUBLICATIONS

Hasan A, Pokeza N, Shaw L, Lee H, Lazzaro D, Chintala H, Rosenbaum D, Grant MB, Chaqour B. The matricellular protein cysteine-rich protein 61 (CCN1/ Cyr61) enhances physiological adaptation of  retinal vessels and reduces pathological neovascularization associated with Ischemic retinopathy. J. Biol. Chem. 2011. (In Press). PMID: 21212276.

Caballero S, Yang R, Grant MB, Chaqour B. Selective blockade of cytoskeletal actin remodeling reduces experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2010. (In Press) PMID: 21178140.

Hanna M, Liu H, Amir J, Sun L, Morris SW, Siddiqui MAQ, Lau LF and Chaqour B. Mechanical regulation of the proangiogenic Factor CCN1/CYR61 gene requires the combined activities of the myocardin-related transcription factor (MRTF)-A and CBP  histone acetyl transferase. J. Biol. Chem. 284(34):23125-36. 2009.

Espinoza-Derout J, Wagner M, Salciccioli L, Lazar JM, Bhaduri S, Mascareno E, Chaqour B, Siddiqui MA.

Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1.Circ Res. 19;104(12):1347-54, 2009.

Yang R, Liu H, Amir J, and Chaqour B. Mechanical Stretch Activates a Program of Genes Functionally Involved in Paracrine Signaling of Angiogenesis. Physiol. Genomics. 12 (36):1-14, 2008.

Liu H, Yang R, Tinner B, Choudhry A, Schutze N, Chaqour B. Cysteine-rich protein 61      and       connective tissue growth factor induce de-adhesion and anoikis of retinal pericytes.   Endocrinology, 149(4):1666-77. 2008.

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. Cradiovas. Res. 75(1): 129-38, 2007.

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, 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.

Yang R, Liu H, Chaqour B. Matrix Metalloproteinase-2 Expression and Apoptogenic Activity in Retinal Pericytes: Implications in Diabetic Retinopathy. An. N. Y. Acad. Sci. 1103: 196-201, 2007.

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. 281(29): 20608-20622, 2006.

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.

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(6):2344-54. 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, K.H, 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.

Tamura I, Rosenbloom J, Macarak E and Chaqour B. Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways. Am. J. Physiol. (Cell Physiol) 281: C1524-C1532. 2001.

List of Publications (Pub Med)