SUNY Downstate Health Sciences University
Department of Cell Biology
Brahim Chaqour, PhD
Department of Cell Biology
Tel: (718) 270-8285 • Fax: (718) 270-3732
- M.Sc.: University of the Sciences of Nancy
- M.e.d.: Biomedical Engineering, National Polytech Institute of Lorraine
- PhD: University of Biomedical Sciences, College of Medicine, Reims-Champagne-et-Ardennes
Occupational History – Academic Appointments:
- Professor, Anatomy and Cell Biology – SUNY Downstate Med Center (Secondary appointment in Dept of Ophthalmology)
- Principal Investigator – SUNY Eye Institute
- Director / Coordinator Histology / Virtual Microscopy Teaching Program in Foundations of Medicine, College of Medicine, SUNY Downstate
- Associate Professor – Anatomy and Cell Biology, SUNY Downstate Med Center
- Assistant Professor – Anatomy and Cell Biology, University of Pennsylvania
- Research Fellow – Anatomy and Histology, University of Pennsylvania
Remodeling and homeostasis of the extracellular matrix: implications for fibrotic and vascular 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., trauma, tissue overdistension/stretch, hemodynamic or pressure overload and shear stress deformation) or chemical stresses imparted by hypoxia, hyperoxia, hyperglycemia, hyperlipidemia and/or ischemia. These studies have direct clinical implications in congenital and acquired diseases of the nervous, cardiovascular and digestive systems e.g., Cardiovascular diseases, diabetes, obstructive diseases, microangiopathies as well as in tumorigenesis.
One aspect of the research work in the Chaqour lab is on investigating 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. Specifically, our studies examine how and why the coordinated or dysregulated expression of growth, angiogenic, and fibrotic factors affects (i) stem cell commitment to specific lineage, (ii) differentiation and growth of tissue, (iii) formation or dissolution of the extracellular matrix which provides the mechanical scaffolding within which organs and tissues are assembled/built and (iii) vascularization to meet the metabolic demands and allow tissue perfusion.
We have identified a group of 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, Wnt and Hippo 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 major focus of our studies is on the development of blood vessels in the eye and how they change in diseases like diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity. The focus is on how these naturally optimized CCN molecules that regulate/stimulate the formation of normal blood vessels and fine-tune the activity of naturally occurring activators and inhibitors of angiogenesis, can be used in a therapeutic context. Understanding the molecular bases of their functioning will help develop therapies to prevent blood vessel occlusion and obliteration and inhibit the growth of abnormal vessels in the retina and choroid, a major cause of blindness associated with retinopathy of prematurity (https://www.nei.nih.gov/health/rop), diabetic retinopathy (https://www.nei.nih.gov/health/diabetic) and age-related macular degeneration.
We are using a wide variety of biochemical, molecular biological and immunohistological approaches including genome-wide profiling microarrays, RNA and miRNA seq, transgenic and conditional knock-out animals, CRISPR 9, microRNA target identification and genetic models of specific miRNA deficiency to tease out the proper effects of the CCN proteins in reprogramming both gene expression and cellular phenotypes.
Sources of Funding:
- National Institutes of Health
- Research to Prevent Blindness Foundation
- Chaqour J, Lee S, Ravichandra A, Chaqour B. Abscisic acid - an anti-angiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages. J Cell Science 131(3): 1-13, 2018. http://jcs.biologists.org/content/early/2018/01/03/jcs.210492
- Lee S, Elaskandrany M, Lau LF, Lazzaro D, Grant MB and Chaqour B. Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy. Scientific reports, 7(1):1405, 1-15., 2017. www.nature.com/articles/s41598-017-01585-8
- Lee S, Elaskandrany M, Ahad A and Chaqour B. Analysis of CCN Protein Expression and Activities in Vasoproliferative Retinopathies. Methods in molecular biology, 1489:543-556, 2017.
- Chaqour B. Regulating the regulators of angiogenesis by CCN1 and taking it up a Notch. J of cell communication and signaling, 10(3):259-261, 2016.
- Jadhav V, Luo Q, M Dominguez J 2nd, Al-Sabah J, Chaqour B, Grant MB, Bhatwadekar AD. Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF). PloS one, 11(9):e0163367, 2016.
- Chintala H, Krupska I, Yan L, Lau L, Grant B and Chaqour B. The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling. Development, 142(13):2364-74. 2015. http://dev.biologists.org/content/142/13/2364.long
- Krupska I, Bruford EA and Chaqour B. Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities. Hum Genomics, 9(1):24, 1-13, 2015.
- Yan L, Lee S, Lazzaro D, Aranda J, Grant M and Chaqour B. Single and compound knock-outs of microRNA (miRNA)-155 and its angiogenic gene target CCN1 in mice alter vascular and neovascular growth in the retina via resident microglia. J. Biol Chem. 290(38):23264-81, 2015. http://www.jbc.org/content/290/38/23264.full.pdf
- Bhatwadekar AD, Yan Y, Stepps V, Hazra S, Korah M, Bartelmez S, Chaqour B and Grant MB. miR-92a Corrects CD34+ Cell Dysfunction in Diabetes by Modulating Core Circadian Genes Involved in Progenitor Differentiation. Diabetes, 64(12):4226-37, 2015.
- Agrawal S, Chaqour B. MicroRNA signature and function in retinal neovascularization World. J. Biol. Chem. 2014 Feb 26;5(1):1-11. 2014.
- Chaqour, B. Molecular control of vascular development by the matricellular proteins CCN1 (Cyr61) and CCN2 (CTGF). Trends Dev Biol. 7:59-72. 2013.
- Choi J., Lin A., Shrier E., Lau L.F., Grant M., Chaqour B. Degradome Products of the Matricellular Protein CCN1 as Modulators of Pathological Angiogenesis in the Retina. J. Biol. Chem. 9;288(32):23075-89. 2013. http://www.jbc.org/content/288/32/23075.full.pdf
- Chaqour B. New Insights into the Function of the Matricellular CCN1: an Emerging Target in Proliferative Retinopathie. J. Ophthal. Vis. Res. 8 (1). 77-82. 2013.
- Yan L., Chaqour B. Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy. J. Cell Commun. Signal. 7(4):253-63, 2013.
- Chintala H, Liu H, Parmar R, Kamalska M, Kim YJ, Lovett D, Grant MB, Chaqour B. Connective tissue growth factor regulates retinal neovascularization through p53-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene. J. Biol. Chem., 23;287(48):40570-40585. 2012. http://www.jbc.org/content/287/48/40570.full.pdf
- Hong P, Chen K, Huang B, Liu M, Cui M, Chaqour B, Pan, Barton ER, Jiang XC, Siddiqui MA. HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration. J. Clin. Invest. 122(11):3873-87. 2012. http://www.jci.org/articles/view/62818
- 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. 18;286(11):9542-54. 2011.
- Caballero S, Yang R, Grant MB, Chaqour B. Selective blockade of cytoskeletal actin remodeling reduces experimental choroidal neovascularization. Invest. Ophthalmol. Vis. Science. 16;52(5):2490-6. 2011.
- 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. 2010. http://www.jbc.org/content/284/34/23125.full.pdf
- 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. http://physiolgenomics.physiology.org/content/physiolgenomics/36/1/1.full.pdf
- 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. Cardiovascular 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. http://www.jbc.org/content/281/29/20608.full.pdf
- 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. http://www.jbc.org/content/278/16/13847.full.pdf
- 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.
Other Services - National and Internatioal Review Committees
- NIH Peer Review Committee – NIH study sections: Ad hoc reviewer
- Grant Review Panel Member of Health Research Board of Ireland
- Grant Review Panel Research Council of Canada
- Grant Review Panel Imperial College of London
- Grant Review Panel the Netherlands Organization for Health Research and Development
- Journal Reviewer/Referee for: PNAS, J Biol Chem, J Clin Invest, Mol Biol Cell, J Cell Science, IOVS, Am J Pathology, Am J Physiol, Physiol, Genomics, Cancer Letters, etc.