Research – Murphy-Ullrich Lab

Current Research Projects, Disease, and Focus Areas Include:

i) Understanding the role of thrombospondin-1 (TSP-1)-mediated activation of latent TGF-β in the bone marrow tumor microenvironment in multiple myeloma. Current projects are focused on examining mechanistic links between the TSP-1/TGF-β axis and drug resistance and tumor immunosuppression. This work has been funded by the American Society for Hematology and by NIH/NCI. Current studies are funded by the Alabama Drug Discovery Alliance.

Representative Citations:

Bailey Dubose K, Zayzafoon M, Murphy-Ullrich JE. Thrombospondin-1 inhibits osteogenic differentiation of human mesenchymal stem cells through latent TGF-β activation. Biochem Biophys Res Commun. 2012 Jun 8;422(3):488-93. doi:10.1016/j.bbrc.2012.05.020. Epub 2012 May 11. PMID: 22583901; PMCID: PMC3372697.

Lu A, Pallero MA, Lei W, Hong H, Yang Y, Suto MJ, Murphy-Ullrich JE. Inhibition of Transforming Growth Factor-β Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma. Am J Pathol. 2016 Mar;186(3):678-90. doi: 10.1016/j.ajpath.2015.11.003. Epub 2016 Jan 20. PMID: 26801735; PMCID: PMC4816696.

Murphy-Ullrich JE, Suto MJ. Thrombospondin-1 regulation of latent TGF-β activation: A therapeutic target for fibrotic disease. Matrix Biol. 2018 Aug;68-69:28-43. doi: 10.1016/j.matbio.2017.12.009. Epub 2017 Dec 27. PMID: 29288716; PMCID: PMC6015530.

ii) Elucidating the relationship between cyclic mechanical strain in posterior eye cells (scleral fibroblasts, lamina cribrosa cells), the TSP-1/TGF-β axis, and scleral and optic nervehead remodeling in glaucoma. This work is funded by NIH/NEI.

Representative Citations:

Qu J, Chen H, Zhu L, Ambalavanan N, Girkin CA, Murphy-Ullrich JE, Downs JC, Zhou Y. High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation. Invest Ophthalmol Vis Sci. 2015 Dec;56(13):7821-30. doi: 10.1167/iovs.15-17848. PMID: 26658503; PMCID: PMC4682490.

Murphy-Ullrich JE, Downs JC. The Thrombospondin1-TGF-β Pathway and Glaucoma. J Ocul Pharmacol Ther. 2015 Sep;31(7):371-5. doi: 10.1089/jop.2015.0016. Epub 2015 May 29. PMID: 26352161; PMCID: PMC7366264.

Wallace DM, Murphy-Ullrich JE, Downs JC, O’Brien CJ. The role of matricellular proteins in glaucoma. Matrix Biol. 2014 Jul;37:174-82. doi: 0.1016/j.matbio.2014.03.007. Epub 2014 Apr 12. PMID: 24727033.

iii) Pursuing drug development of small molecule TSP-1/TGF-β antagonists for treatment of fibrotic diseases and cancer. We are developing peptide and non-peptide small molecules to mimic the LSKL tetrapeptide from the LAP (latency associated peptide) of latent TGF-β to block TSP-1 binding to the latent complex to prevent activation. This work is a collaboration with Dr. Mark J. Suto at Southern Research (https://southernresearch.org/) and his drug discovery team. The work has been supported by NIH/NCI and the Alabama Drug Discovery Alliance.

Representative Citations:

Suto MJ, Gupta V, Mathew B, Zhang W, Pallero MA, Murphy-Ullrich JE. Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β. ACS Med Chem Lett. 2020 May 7;11(6):1130-1136. doi: 10.1021/acsmedchemlett.9b00540.PMID: 32550992; PMCID: PMC7294719.

Murphy-Ullrich JE. Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease. J Histochem Cytochem. 2019 Sep;67(9):683-699. doi: 10.1369/0022155419851103. Epub 2019 May 22. PMID: 31116066; PMCID: PMC6713974.

Sweetwyne MT, Murphy-Ullrich JE. Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol. 2012 Apr;31(3):178-86. doi: 10.1016/j.matbio.2012.01.006. Epub 2012 Jan 14. PMID: 22266026; PMCID: PMC3295861.

Lu A, Miao M, Schoeb TR, Agarwal A, Murphy-Ullrich JE. Blockade of TSP1-dependent TGF-β activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am J Pathol. 2011 Jun;178(6):2573-86. doi:10.1016/j.ajpath.2011.02.039. PMID: 21641382; PMCID: PMC3124297.

Belmadani S, Bernal J, Wei CC, Pallero MA, Dell’italia L, Murphy-Ullrich JE, Berecek KH. A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. Am J Pathol. 2007 Sep;171(3):777-89. doi: 10.2353/ajpath.2007.070056. Epub 2007 Jul 19. PMID: 17640965; PMCID: PMC1959499.

Young GD, Murphy-Ullrich JE. Molecular interactions that confer latency to transforming growth factor-beta. J Biol Chem. 2004 Sep 3;279(36):38032-9. doi: 10.1074/jbc.M405658200. Epub 2004 Jun 18. PMID: 15208302.

Murphy-Ullrich JE, Poczatek M. Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69. doi: 10.1016/s1359-6101(99)00029-5. PMID: 10708953.

Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem. 1999 May 7;274(19):13586-93. doi: 10.1074/jbc.274.19.13586. PMID:10224129.

Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998 Jun 26;93(7):1159-70. doi: 10.1016/s0092-8674(00)81460-9. PMID:9657149.

Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, Murphy-Ullrich JE. Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem. 1995 Mar 31;270(13):7304-10. doi: 10.1074/jbc.270.13.7304. PMID: 7706271.

Schultz-Cherry S, Murphy-Ullrich JE. Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol. 1993 Aug;122(4):923-32. doi: 10.1083/jcb.122.4.923.Erratum in: J Cell Biol 1993 Sep;122(5):following 1143. PMID: 8349738; PMCID: PMC2119591.

Patents

US Patent Serial No. 9,353,149 (filed 05/09/2014 issued May 31, 2016) “Compounds, methods, and compositions for the treatment of diseases through inhibiting TGF-beta.” Mark J. Suto and Joanne E. Murphy-Ullrich

US Patent 10,653,682 (patent filed 10/26/18, issued 5/19/20) “Oxadiazoles and thiadiazoles as TGF-beta inhibitors” Suto, Gupta, Mathew, and Murphy-Ullrich

Provisional patent US-2019127420-A1, priority date 10/26/17 “Dipeptide analogues as TGF-beta inhibitors” Suto and Murphy-Ullrich (patent filed 10/26/18)

iv) To investigate the role of the endoplasmic reticulum (ER) chaperone and calcium regulatory protein, caleticulin, in mediating TGF-β transcriptional regulation of ECM proteins in fibrotic diseases driven by ER and oxidative stress, including vascular injury and diabetic nephropathy. This work was supported by a grant from the Department of Defense.

Representative Citations:

Lu A, Pallero MA, Owusu BY, Borovjagin AV, Lei W, Sanders PW, Murphy-Ullrich JE. Calreticulin is important for the development of renal fibrosis and dysfunction in diabetic nephropathy. Matrix Biol Plus. 2020 Apr 3; 8:100034. doi: 10.1016/j.mbplus.2020.100034. PMID: 33543033; PMCID: PMC7852315.

Owusu BY, Zimmerman KA, Murphy-Ullrich JE. The role of the endoplasmic reticulum protein calreticulin in mediating TGF-β-stimulated extracellular matrix production in fibrotic disease. J Cell Commun Signal. 2018 Mar;12(1):289-299. doi: 10.1007/s12079-017-0426-2. Epub 2017 Oct 28. PMID: 29080087; PMCID: PMC5842189.

Zimmerman KA, Xing D, Pallero MA, Lu A, Ikawa M, Black L, Hoyt KL, Kabarowski JH, Michalak M, Murphy-Ullrich JE. Calreticulin Regulates Neointima Formation and

Collagen Deposition following Carotid Artery Ligation. J Vasc Res. 2015;52(5):306-20. doi: 10.1159/000443884. Epub 2016 Feb 25. PMID: 26910059; PMCID: PMC4816666.

Zimmerman KA, Graham LV, Pallero MA, Murphy-Ullrich JE. Calreticulin regulates transforming growth factor-β-stimulated extracellular matrix production. J Biol Chem. 2013 May 17;288(20):14584-98. doi:10.1074/jbc.M112.447243. Epub 2013 Apr 5. PMID: 23564462; PMCID: PMC3656311.

Van Duyn Graham L, Sweetwyne MT, Pallero MA, Murphy-Ullrich JE. Intracellular calreticulin regulates multiple steps in fibrillar collagen expression, trafficking, and processing into the extracellular matrix. J Biol Chem. 2010 Mar 5;285(10):7067-78. doi: 10.1074/jbc.M109.006841. Epub 2009 Dec 31. PMID:20044481; PMCID: PMC2844156. PMCID: PMC4816666.

v) Collaborative studies We are examining gut bacteria regulation of TGF-β activation and relation to intestinal inflammation and cancer with Dr. Yi Xu at Texas A&M Institute of Biosciences and Technology (NIH- funded), with Dr. Michael Albro at Boston University on studies to design novel latent TGF-β releasing contructs for cartilage repair (NSF-funded), and with Dr. Kate Keller, Oregon Health & Sciences University, to study the role of TSP-1 variants and antagonists of TSP-1/TGF-β in trabecular outflow in glaucoma.

Important Links

American Society for Matrix Biology

www.asmb.net

@amsocmatbio

#ECMatrix

International Society for Matrix Biology

www.ismb.org

@IntSocMatBio

FASEB Scientific Resarch Conference on Matricellular proteins

https://src.faseb.org/matricellular-proteins

https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202000364

Matrix Biology/Matrix Biology Plus

#MatrixBiology https://www.journals.elsevier.com/matrix-biology

#MatrixBiologyPlus https://www.sciencedirect.com/journal/matrix-biology-plus