Pattabiraman Lab
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The Pattabiraman Lab studies the pathophysiology and treatment paradigms for primary open-angle glaucoma (POAG). The lab focuses on the following three lines of research:
- Understanding the role of mechanobiology in ocular tissues and importantly in the regulation of aqueous humor outflow regulation. This project mainly deals with examining the molecular mechanisms involved in the regulation of extracellular matrix production, remodeling, and degradation in the aqueous humor outflow pathway.
- Understanding the role of chaperone protein clusterin in aqueous humor outflow physiology. Clusterin is a secretory chaperone protein found in the aqueous humor and produced by trabecular meshwork, iris, ciliary body and other ocular tissues. Clusterin plays an important role in regulating cell-cell adhesion and cell-substratum/matrix interactions. The levels of clusterin mRNA has been shown to be lowered in POAG and the biochemical and functional interactome of genes implicated in ocular hypertension reveal a putative linkage of clusterin gene in the POAG pathogenesis. Yet very little is known about the role of clusterin in outflow biology. The lab studies the mechanistic role of clusterin in IOP regulation.
- Understanding the structure and function of trabecular outflow tissues differ between people of African and European Descent. Lacking is knowledge of differences in the ECM architecture and compaction in normal and POAG eyes in AD and ED. Researchers couple structure of the TM (molecular and cellular) with its function (outflow facility) in non-glaucomatous and glaucomatous donor eyes to identify differences in ocular physiology among AD and ED.
Research Focus and Questions
The actin cytoskeleton contractility and extracellular matrix (ECM)-based tissue stiffness in the trabecular meshwork (TM) is known to modulate the aqueous humor (AH) drainage and intraocular pressure (IOP). In POAG, characteristic changes occur in the tissue structure of the AH outflow pathway and the major changes are increased contractility, excessive alterations in ECM organization in the JCT-TM region, and accumulation of sheath-like plaque materials leading to altered tissue stiffness. Current IOP lowering strategies, target the cytoskeleton and lower ECM accumulation.
The Pattabiraman Lab studies the significant knowledge gaps in the contribution of the actin and ECM in the regulation of outflow resistance, such as: the regulatory controls of actin cytoskeleton-based TM cellular tension; the molecular basis for ECM production, degradation, and clearance in the AH outflow pathway and the contributions of ECM-based tissue stiffness in the regulation of IOP; and the factors leading to actin cytoskeleton-ECM dysregulation in TM resulting in IOP elevation.
Additionally, researchers are identifying and developing novel therapeutics for IOP lowering.
Cell adhesion complexes, which bridge the intracellular cytoskeleton and the ECM, act as key force-sensing and -transducing units in cells. Cell adhesive interactions and cell-cell junctions influence the permeability characteristics of fluid flow through cells. Clusterin is known to regulate cell-matrix interactions as well as act as a chaperone protein to stabilize cathepsin k (CTSK) and CTSK can hydrolyze ECM. Researchers explored the role of the clusterin-CTSK axis in the regulation of ECM and IOP.
The lab studies the role of CTSK in IOP regulation. CTSK is an ECM degradating enzyme mainly found in osteoclasts. The problem that results in elevated IOP has increased ECM deposition. In a proof-of-concept study to show that by augmenting CTSK, we can decrease ECM, and to signify the importance of CTSK and ECM in regulating IOP, we inhibited CTSK using a pharmacological inhibitor balicatib, to significantly induce ocular hypertension. Contrarily increasing CTSK function decreased ECM and subsequently the IOP. Therefore, signifying the functional importance of CTSK activation and its availability, which can provide us with a novel therapeutic strategy to lower IOP.
We are finding that clusterin regulates actin cytoskeleton - ECM interactions in the TM and the maintenance of IOP, thus making clusterin an interesting target to reverse elevated IOP.
Apart from HS, clusterin/apolipoprotein J can also bind to other receptors such as TGFβR1, TGFβR2, VLDLR, LRP2, and LRP8. What is the signaling relevance of such binding?
TM cell membrane plays an important role in modulating cellular properties. We are working towards identifying the significance of maintaining membrane and cellular cholesterol levels and cellular communication for achieving IOP homeostasis.
Lacking is the knowledge of differences in the ECM architecture and compaction in normal and POAG eyes in AD and ED. We will couple the structure of the TM (molecular and cellular) with its function (outflow facility) in non-glaucomatous and glaucomatous donor eyes to identify differences in ocular physiology among AD and ED.
Research Team
The research in the Pattabiraman Lab is carried out by a team of intelligent and smart minds including postdoctoral fellows, graduate students, undergraduates, medical students and school students. Led by Padmanabhan Pattabiraman, PhD, the lab includes: Avinash Soundararajan (postdoctoral fellow); Ting Wang (PhD candidate); Chevy Singh (medical student); Jamie Surgent-Nahay (medical student); Zion Goldman (research assistant); and Anoop Magesh (research assistant).
Padmanabhan Pattabiraman |
Avinash Soundararajan |
Ting Wang |
Collaborators
Tim Corson, Associate Professor, Department of Ophthalmology, Indiana University School of Medicine
Michael Weiss, Professor, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine
Brian Blagg, Professor, Department of Chemistry and Biochemistry, University of Notre Dame
Carol Toris, Professor, Department of Ophthalmology, University of Nebraska
Sanjoy Bhattacharya, Professor of Ophthalmology, Miami Integrative Metabolomics Research Center, University of Miami
Michael Weiss, Professor, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine
Brian Blagg, Professor, Department of Chemistry and Biochemistry, University of Notre Dame
Carol Toris, Professor, Department of Ophthalmology, University of Nebraska
Sanjoy Bhattacharya, Professor of Ophthalmology, Miami Integrative Metabolomics Research Center, University of Miami
Publications
Toris CB, Pattabiraman PP, Tye G, Samuelson TW, Rhee DJ. Outflow Facility Effects of Three Schlemm Canal MIGS. Ophthalmology Glaucoma, 2020 3(2) 114-121.
Soundararajan A*, Ghag SA*, Vuda SS, Wang T, Pattabiraman PP. Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway. Cells. 2021 Oct 24;10(11). doi: 10.3390/cells10112864. PMID: 34831087. (*equal contribution)
Toris C.B., Tye G, Pattabiraman P. Changes in Parameters of Aqueous Humor Dynamics Throughout Life. In: Guidoboni G., Harris A., Sacco R. (eds) Ocular Fluid Dynamics. Modeling and Simulation in Science, Engineering and Technology. Birkhäuser, Cham. (2019) p. 161-190
Padmanabhan PP, and Soundararajan A. Rho kinase inhibition – A therapeutic intervention for glaucoma. Glaucoma Toward Solving the Problem 2020 to 2022. Edited By Knepper and Samples: Kugler 2020
Sai Supriya Vuda1, Haarika Reddy, Jeffrey Rabinowitz, Padmanabhan P Pattabiraman; Cathepsin K, a lysosomal protease, modulates expression and availability of transforming growth factor β2 (TGFβ2) and extracellular matrix remodeling in trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3429. (1ARVO/NEI TRAVEL AWARD WINNER)
Jeffrey Rabinowitz, Haarika Reddy, Padmanabhan P Pattabiraman; Clusterin acts as an endogenous statin by controlling the expression and nuclear translocation of sterol regulatory-element binding protein (SREBP) in trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3462.
Avinash Soundararajan, Joshua William Buzzard, Haarika Reddy, Min Hyung Kang, Douglas J Rhee, Padmanabhan P Pattabiraman; Regulation and role of clusterin, a secretory chaperone protein, on intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3208. (ARVO Talk)
Ting Wang, Jeffery Rabinowitz, Haarika Reddy, Cristina Ferreira, Padmanabhan Pattabiraman. Clusterin modulates lipid biogenesis in trabecular meshwork. American Society for Cell Biology (Virtual Meeting) December 2020
Sachin Anil Ghag, Padmanabhan Pattabiraman. Dexamethasone Inhibits Canonical Notch Signaling Pathway in Trabecular Meshwork. American Society for Cell Biology (Virtual Meeting) December 2020
C Singh, D Jusufbegovic, J Lind, P Pattabiraman. Glaucoma and Diabetes: A Sweet Connection. Proceedings of IMPRS, 2020
Sachin Anil Ghag1, Padmanabhan P Pattabiraman; Role of Notch Signaling Pathway in Steroid Induced Glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):492. (1ARVO/NEI TRAVEL AWARD WINNER)
Ting Wang1, Jeffrey Rabinowitz, Padmanabhan P Pattabiraman; Inactivation of the Transcription Factor Sterol Regulatory Element Binding Protein (SREBP) Lowers Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2021;62(8):476. (1ARVO/NEI TRAVEL AWARD WINNER)
Avinash Soundararajan1, Padmanabhan P Pattabiraman; Mechanistic Role of Clusterin in Extracellular Matrix remodeling and Intraocular Pressure Homeostasis. Invest. Ophthalmol. Vis. Sci. 2021;62(8):475. (1ARVO/NEI TRAVEL AWARD WINNER)
Chevy Singh, Avinash Soundararajan, Denis Jusufbegovic, John Lind, Padmanabhan P Pattabiraman; Alterations in Gene Expression of Human Trabecular Meshwork Cells in Response to Hyperglycemic Conditions. Invest. Ophthalmol. Vis. Sci. 2021;62(8):480.
Padmanabhan P Pattabiraman, Avinash Soundararajan, Ting Wang, Aruna Wijeratne, Amber Mosely; Mechanical Stretch Increases Cholesterol Biosynthesis in Human Trabecular Meshwork. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1639.
Sai Supriya Vuda1, Sachin Anil Ghag, Padmanabhan P Pattabiraman; Cathepsin K Activity in Trabecular Meshwork Outflow Pathway Regulates Intraocular Pressure Homeostasis. Invest. Ophthalmol. Vis. Sci. 2021;62(8):477. (1ARVO/NEI TRAVEL AWARD WINNER)