SUNY Downstate Health Sciences University
Department of Cell Biology
Brahim Chaqour, PhD
Department of Cell Biology
Department of Ophthalmology
Tel: (718) 270-8285
Academic Background - Education:
- M.Sc., University of the Sciences (Vandoeuvre-les-Nancy)
- M.e.d., Biomedical Engineering, Institut National Polytechnique de Lorraine
- Ph.D., University of Reims-Champagne-et-Ardennes, College of Medicine
Occupational History – Academic Appointments:
- Professor, Anatomy and Cell Biology – SUNY Downstate Medical Center
- Professor, Ophthalmology – SUNY Downstate Medical Center
- Principal Investigator – SUNY Eye Institute
- Director / Coordinator Histology / Virtual Microscopy Teaching Program of Foundations 1 and 2 of Medicine, College of Medicine, SUNY Downstate Medical Center
- 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 vascular and fibrovascular diseases.
Research Interests and sources of funding:
Overall view: 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 in nature (e.g., trauma, tissue overdistension/stretch, shear stress deformation, stiffness of the extracellular matrix, and pressure overload) 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., diabetic microangiopathies, obstructive diseases, as well as in tumorigenesis.
ECM proteins and mechanobiology: 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. 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 disease states of the retina, brain, heart and lung, 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 YAP 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.
Matricellular proteins in microvascular diseases of the eye: Another major focus in the Chaqour lab is on the mechanisms underlying progressive microvascular pathologies associated with ischemic and neurodegenerative diseases. Abnormalities in microvessel growth and barrier function contribute to the onset and progression of numerous diseases of the CNS. In the retina, disorders of small blood vessel growth and integrity are responsible for vision loss in ischemic retinopathies (e.g., diabetic retinopathy, wet age-related macular degeneration and retinopathy of prematurity). These pathologies are caused by damages to endothelial cells, impairment of the blood-retina barrier, inflammation and inadequate vascular repair. Similarly, defects in endothelial cells impair blood-brain barrier function and immunity, and promote cerebrovascular and neurodegenerative diseases.
The focus of our research is on the mechanisms whereby the CCN molecules regulate the formation of normal blood vessels and fine-tune the activity of naturally occurring activators and inhibitors of angiogenesis. Our studies showed that CCN protein signals are shared with cells’ response to extracellular matrix stiffness suggesting that the CCN proteins function to modulate cells’ deformability or stiffness. We are using a wide variety of biochemical, molecular biological and immunohistological approaches including genome-wide profiling microarrays, RNA, miRNA, and single cell RNA seq, transgenic and conditional knock-out animals, CRISPR 9, microRNA target identification and genetic models of specific miRNA deficiency to tease out the mechanisms whereby CCN protein and their gene regulatory network regulate the cells’ microenvironment and reprogram both gene expression and cellular phenotypes and behavior in physiological and pathological conditions.
A better understanding of the regulation and mode of action of CCN protein will be useful in developing specific gain- or loss-of-function strategies to inhibit the growth of abnormal vessels in the retina, vitreous and choroid; a major cause of blindness in retinopathy of prematurity (https://www.nei.nih.gov/health/rop), diabetic retinopathy (https://www.nei.nih.gov/health/diabetic), age-related macular degeneration and Norrie disease (https://ghr.nlm.nih.gov/condition/norrie-disease). Our studies have tremendous potential to fill the large unmet clinical need for therapy to enhance reendothelialization after vascular injury in ocular (and non-ocular) microvascular diseases.
Current and/or previous sources of funding:
- National Institutes of Health -National Eye Institute
- National Institutes of Health -NIDDK
- Research to Prevent Blindness Foundation
- Lee S, Ahad A, Luu M, Moon S, Caesar J, Cardoso WV, Grant MB, Chaqour B. CCN1-Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis. Mol Cell Biol. 39(18), 107-19. 2019.
- Chaqour B. Caught between a "Rho" and a hard place: are CCN1/CYR61 and CCN2/CTGF the arbiters
of microvascular stiffness?. J Cell Commun Signal. 2019 Aug 2;. doi: 10.1007/s12079-019-00529-3. [Epub ahead
of print] Review. PubMed PMID: 31376071.
- 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.
Lecturer: Foundations 1 – College of Medicine
Endocrine Subunit- Endocrine System Physiol, Embryology and Pathology
Lecturer and Facilitator: Histology and Virtual Microscopy (VM)
Foundations 1: Units 1: 2, 3, 4
Foundations 2 : Unit 5
Director and Coordinator of Histo-VM labs - Units 1, 2, 3 and 5
Committee Membership/University Services
- Dean’s Initiative on Research Investment Committee
- Sub-Committee on Educational Policy and Curriculum (CEPC)
- Dean’s Initiative on Research Investment Committee
- Executive Committee of the School of Graduate Studies
- Faculty and Student Health Advisory Committee
- Executive Committee of the College of Medicine (member)
- Advisory Committee on Research (Research Subcommittee)
- Executive Committee of the School of Graduate Studies (member)
NIH Peer Review Committees - Ad hoc Reviewer (2012-2019):
- Diseases and Pathophysiology of the Visual System Study Section
- Physiology and Pathobiology of Cardiovascular and Respiratory System Study Section
- Cell Biology, Developmental Biology, and Bioengineering Study Section
- Clinical Neuroimmunology and Brain Tumors (CNBT) Study Section
NIH Peer Review Committee - Member (2019-Present):
- Diseases and Pathophysiology of the Visual System Study Section
International Review Committees (2006-Present):
- Imperial College of London
- Research Board of Ireland
- Research Council of Canada
- The Netherlands Organization for Research and Development
- National Medical Research Council -Ministry of Health of Singapore
Advisory Scientific Committee:
- Advisory Scientific Committee and Counsel – ICCNS