Affiliation

Dorin-Bogdan Borza Ph.D. Affiliation: Meharry Medical College Microbiology and Immunology "Infectious and Immunological Diseases" Title: Assistant Professor Rank: Assistant Professor Address: 1005 Dr. D.B.Todd, Jr. Blvd Nashville, TN 37208 Contact: Email: [e-mail] Telephone: [phone]

Narrative

My research leverages my multi-disciplinary training in biochemistry, immunology and nephrology to elucidate the molecular mechanisms underlying the etiology and pathogenesis of antibody (Ab)-mediated glomerular diseases. I have extensive experience and expertise studying the biochemistry of type IV collagen of the glomerular basement membrane (GBM) and its role in Goodpasture disease (anti-GBM antibody nephritis) and Alport syndrome. My research has used the paradigm of Goodpasture disease to address the mechanisms eliciting abnormal immune responses against a345(IV) collagen and how the resulting anti-GBM Abs mediate glomerulonephritis. Overall, my work has elucidated the organization of Goodpasture autoantigen, providing the framework for understanding how tolerance to collagen IV is established in health and breached in anti-GBM disease. I have established how the assembly of a345(IV) collagen into quaternary structures hides cryptic B cell auto-epitopes while also creating new quaternary epitopes, thereby shaping immune tolerance and autoimmunity to collagen IV. My lab has also developed a robust mouse model faithfully recapitulate the clinical and morphologic hallmarks of human membranous nephropathy, in which subepithelial immune complexes induce severe albuminuria and nephrotic syndrome in a manner dependent on complement activation and the neonatal Fc receptor (FcRn). To further elucidate how human IgG autoAbs cause glomerular injury, I have recently developed a novel functional assay for complement activation by human autoAbs bound to their target antigen, which provide a model for glomerular immune complexes. In summary, I have established a strong track record of successful, productive, innovative and collaborative research in the area of Ab-mediated kidney disease.

Publications

1.	Laskowski J, Renner B, Le Quintrec M, Panzer S, Hannan JP, Ljubanovic D, Ruseva MM, Borza DB, Antonioli AH, Pickering MC, Holers VM, Thurman JM. Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury. Kidney Int. 2016 Jul; 90(1):109-22.	PubMed
2.	Borza DB. Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy. Front Immunol. 2016; 7:157.	PubMed
3.	Sueki H, Sato Y, Ohtoshi S, Nakada T, Yoshimura A, Tateishi C, Borza DB, Fader W, Ghohestani RF, Hirako Y, Koga H, Ishii N, Tsuchisaka A, Qian H, Li X, Hashimoto T. A Case of Subepidermal Blistering Disease with Autoantibodies to Multiple Laminin Subunits who Developed Later Autoantibodies to Alpha-5 Chain of Type IV Collagen Associated with Membranous Glomerulonephropathy. Acta Derm Venereol. 2015 Jan 29.	PubMed
4.	Gomez IG, MacKenna DA, Johnson BG, Kaimal V, Roach AM, Ren S, Nakagawa N, Xin C, Newitt R, Pandya S, Xia TH, Liu X, Borza DB, Grafals M, Shankland SJ, Himmelfarb J, Portilla D, Liu S, Chau BN, Duffield JS. Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest. 2015 Jan; 125(1):141-56.	PubMed
5.	Borza DB. IgG4-Restricted Anti-Glomerular Basement Membrane Autoantibodies Targeting Quaternary Epitopes of Native a345(IV) Collagen. Am J Kidney Dis. 2014 Jul; 64(1):156-7.	PubMed
6.	Olaru F, Luo W, Suleiman H, St John PL, Ge L, Mezo AR, Shaw AS, Abrahamson DR, Miner JH, Borza DB. Neonatal fc receptor promotes immune complex-mediated glomerular disease. J Am Soc Nephrol. 2014 May; 25(5):918-25.	PubMed
7.	Fidler AL, Vanacore RM, Chetyrkin SV, Pedchenko VK, Bhave G, Yin VP, Stothers CL, Rose KL, McDonald WH, Clark TA, Borza DB, Steele RE, Ivy MT. A unique covalent bond in basement membrane is a primordial innovation for tissue evolution. Proc Natl Acad Sci U S A. 2014 Jan 7; 111(1):331-6.	PubMed
8.	Wang F, Jiang RT, Tantawy MN, Borza DB, Takahashi K, Gore JC, Harris RC, Takahashi T, Quarles CC. Repeatability and sensitivity of high resolution blood volume mapping in mouse kidney disease. J Magn Reson Imaging. 2014 Apr; 39(4):866-71.	PubMed
9.	Borza DB, Zhang JJ, Beck LH, Meyer-Schwesinger C, Luo W. Mouse models of membranous nephropathy: the road less travelled by. Am J Clin Exp Immunol. 2013; 2(2):135-45.	PubMed
10.	Olaru F, Luo W, Wang XP, Ge L, Hertz JM, Kashtan CE, Sado Y, Segal Y, Hudson BG, Borza DB. Quaternary epitopes of a345(IV) collagen initiate Alport post-transplant anti-GBM nephritis. J Am Soc Nephrol. 2013 May; 24(6):889-95.	PubMed
11.	Olaru F, Wang XP, Luo W, Ge L, Miner JH, Kleinau S, Geiger XJ, Wasiluk A, Heidet L, Kitching AR, Borza DB. Proteolysis breaks tolerance toward intact a345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for a345NC1 hexamers. J Immunol. 2013 Feb 15; 190(4):1424-32.	PubMed
12.	Borza DB, Fogo AB. Interstitial mononuclear infiltrates in murine a3(IV)-NC1-induced nephropathy: harbingers of renal failure? Kidney Int. 2012 Nov; 82(9):1033-4; author reply 1034.	PubMed
13.	Ooi JD, Chang J, Hickey MJ, Borza DB, Fugger L, Holdsworth SR, Kitching AR. The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis. Proc Natl Acad Sci U S A. 2012 Sep 25; 109(39):E2615-24.	PubMed
14.	Harrison FE, Best JL, Meredith ME, Gamlin CR, Borza DB, May JM, May JM. Increased expression of SVCT2 in a new mouse model raises ascorbic acid in tissues and protects against paraquat-induced oxidative damage in lung. PLoS One. 2012; 7(4):e35623.	PubMed
15.	Zhang JJ, Malekpour M, Luo W, Ge L, Olaru F, Wang XP, Bah M, Sado Y, Heidet L, Kleinau S, Fogo AB, Borza DB. Murine membranous nephropathy: immunization with a3(IV) collagen fragment induces subepithelial immune complexes and Fc?R-independent nephrotic syndrome. J Immunol. 2012 Apr 1; 188(7):3268-77.	PubMed
16.	Becknell B, Zender GA, Houston R, Baker PB, McBride KL, Luo W, Hains DS, Borza DB, Schwaderer AL. Novel X-linked glomerulopathy is associated with a COL4A5 missense mutation in a non-collagenous interruption. Kidney Int. 2011 Jan; 79(1):120-7.	PubMed
17.	Luo W, Wang XP, Kashtan CE, Borza DB. Alport alloantibodies but not Goodpasture autoantibodies induce murine glomerulonephritis: protection by quinary crosslinks locking cryptic a3(IV) collagen autoepitopes in vivo. J Immunol. 2010 Sep 15; 185(6):3520-8.	PubMed
18.	Pedchenko V, Bondar O, Fogo AB, Vanacore R, Voziyan P, Kitching AR, Wieslander J, Kashtan C, Borza DB, Neilson EG, Wilson CB, Hudson BG. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med. 2010 Jul 22; 363(4):343-54.	PubMed
19.	Summers SA, Steinmetz OM, Li M, Kausman JY, Semple T, Edgtton KL, Borza DB, Braley H, Holdsworth SR, Kitching AR. Th1 and Th17 cells induce proliferative glomerulonephritis. J Am Soc Nephrol. 2009 Dec; 20(12):2518-24.	PubMed
20.	Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St John PL. Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol. 2009 Jul; 20(7):1471-9.	PubMed
21.	Gross O, Borza DB, Anders HJ, Licht C, Weber M, Segerer S, Torra R, Gubler MC, Heidet L, Harvey S, Cosgrove D, Lees G, Kashtan C, Gregory M, Savige J, Ding J, Thorner P, Abrahamson DR, Antignac C, Tryggvason K, Hudson B, Miner JH. Stem cell therapy for Alport syndrome: the hope beyond the hype. Nephrol Dial Transplant. 2009 Mar; 24(3):731-4.	PubMed
22.	Kang JS, Colon S, Hellmark T, Sado Y, Hudson BG, Borza DB. Identification of noncollagenous sites encoding specific interactions and quaternary assembly of alpha 3 alpha 4 alpha 5(IV) collagen: implications for Alport gene therapy. J Biol Chem. 2008 Dec 12; 283(50):35070-7.	PubMed
23.	Ho J, Gibson IW, Zacharias J, Fervenza F, Colon S, Borza DB. Antigenic heterogeneity of IgA anti-GBM disease: new renal targets of IgA autoantibodies. Am J Kidney Dis. 2008 Oct; 52(4):761-5.	PubMed
24.	Shimizu H, Aufschnaiter R, Li L, Sarras MP, Borza DB, Abrahamson DR, Sado Y, Zhang X. The extracellular matrix of hydra is a porous sheet and contains type IV collagen. Zoology (Jena). 2008; 111(5):410-8.	PubMed
25.	Vanacore RM, Ham AJ, Cartailler JP, Sundaramoorthy M, Todd P, Pedchenko V, Sado Y, Borza DB, Hudson BG. A role for collagen IV cross-links in conferring immune privilege to the Goodpasture autoantigen: structural basis for the crypticity of B cell epitopes. J Biol Chem. 2008 Aug 15; 283(33):22737-48.	PubMed
26.	Xu H, Hu F, Sado Y, Ninomiya Y, Borza DB, Ungvari Z, Lagamma EF, Csiszar A, Nedergaard M, Ballabh P. Maturational changes in laminin, fibronectin, collagen IV, and perlecan in germinal matrix, cortex, and white matter and effect of betamethasone. J Neurosci Res. 2008 May 15; 86(7):1482-500.	PubMed
27.	Pozzi A, Jarad G, Moeckel GW, Coffa S, Zhang X, Gewin L, Eremina V, Hudson BG, Borza DB, Harris RC, Holzman LB, Phillips CL, Fassler R, Quaggin SE, Miner JH, Zent R. Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity. Dev Biol. 2008 Apr 15; 316(2):288-301.	PubMed
28.	Borza CM, Borza DB, Pedchenko V, Saleem MA, Mathieson PW, Sado Y, Hudson HM, Pozzi A, Saus J, Abrahamson DR, Zent R, Hudson BG. Human podocytes adhere to the KRGDS motif of the alpha3alpha4alpha5 collagen IV network. J Am Soc Nephrol. 2008 Apr; 19(4):677-84.	PubMed
29.	Borza DB. Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis. Nephron Exp Nephrol. 2007; 106(2):e37-43.	PubMed
30.	Fox MA, Sanes JR, Borza DB, Eswarakumar VP, Fässler R, Hudson BG, John SW, Ninomiya Y, Pedchenko V, Pfaff SL, Rheault MN, Sado Y, Segal Y, Werle MJ, Umemori H. Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell. 2007 Apr 6; 129(1):179-93.	PubMed
31.	Steenhard BM, Freeburg PB, Isom K, Stroganova L, Borza DB, Hudson BG, St John PL, Zelenchuk A, Abrahamson DR. Kidney development and gene expression in the HIF2alpha knockout mouse. Dev Dyn. 2007 Apr; 236(4):1115-25.	PubMed
32.	Kang JS, Kashtan CE, Turner AN, Heidet L, Hudson BG, Borza DB. The alloantigenic sites of alpha3alpha4alpha5(IV) collagen: pathogenic X-linked alport alloantibodies target two accessible conformational epitopes in the alpha5NC1 domain. J Biol Chem. 2007 Apr 6; 282(14):10670-7.	PubMed
33.	Cosgrove D, Kalluri R, Miner JH, Segal Y, Borza DB. Choosing a mouse model to study the molecular pathobiology of Alport glomerulonephritis. Kidney Int. 2007 Apr; 71(7):615-8.	PubMed
34.	Zent R, Yan X, Su Y, Hudson BG, Borza DB, Moeckel GW, Qi Z, Sado Y, Breyer MD, Voziyan P, Pozzi A. Glomerular injury is exacerbated in diabetic integrin alpha1-null mice. Kidney Int. 2006 Aug; 70(3):460-70.	PubMed
35.	Kang JS, Wang XP, Miner JH, Morello R, Sado Y, Abrahamson DR, Borza DB. Loss of alpha3/alpha4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to alpha5alpha6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice. J Am Soc Nephrol. 2006 Jul; 17(7):1962-9.	PubMed
36.	Borza CM, Pozzi A, Borza DB, Pedchenko V, Hellmark T, Hudson BG, Zent R. Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3. J Biol Chem. 2006 Jul 28; 281(30):20932-9.	PubMed
37.	Wang XP, Fogo AB, Colon S, Giannico G, Abul-Ezz SR, Miner JH, Borza DB. Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen. J Am Soc Nephrol. 2005 Dec; 16(12):3563-71.	PubMed
38.	Borza DB, Bondar O, Colon S, Todd P, Sado Y, Neilson EG, Hudson BG. Goodpasture autoantibodies unmask cryptic epitopes by selectively dissociating autoantigen complexes lacking structural reinforcement: novel mechanisms for immune privilege and autoimmune pathogenesis. J Biol Chem. 2005 Jul 22; 280(29):27147-54.	PubMed
39.	Borza DB. Life without histidine-rich glycoprotein: modulation of the hemostatic balance revisited. J Thromb Haemost. 2005 May; 3(5):863-4.	PubMed
40.	Borza DB, Chedid MF, Colon S, Lager DJ, Leung N, Fervenza FC. Recurrent Goodpasture's disease secondary to a monoclonal IgA1-kappa antibody autoreactive with the alpha1/alpha2 chains of type IV collagen. Am J Kidney Dis. 2005 Feb; 45(2):397-406.	PubMed
41.	Borza DB, Shipulina NV, Morgan WT. Effects of histidine-proline-rich glycoprotein on plasminogen activation in solution and on surfaces. Blood Coagul Fibrinolysis. 2004 Oct; 15(8):663-72.	PubMed
42.	Borza DB, Neilson EG, Hudson BG. Pathogenesis of Goodpasture syndrome: a molecular perspective. Semin Nephrol. 2003 Nov; 23(6):522-31.	PubMed
43.	Heidet L, Borza DB, Jouin M, Sich M, Mattei MG, Sado Y, Hudson BG, Hastie N, Antignac C, Gubler MC. A human-mouse chimera of the alpha3alpha4alpha5(IV) collagen protomer rescues the renal phenotype in Col4a3-/- Alport mice. Am J Pathol. 2003 Oct; 163(4):1633-44.	PubMed
44.	Borza DB, Hudson BG. Molecular characterization of the target antigens of anti-glomerular basement membrane antibody disease. Springer Semin Immunopathol. 2003 May; 24(4):345-61.	PubMed
45.	Borza DB, Bondar O, Todd P, Sundaramoorthy M, Sado Y, Ninomiya Y, Hudson BG. Quaternary organization of the goodpasture autoantigen, the alpha 3(IV) collagen chain. Sequestration of two cryptic autoepitopes by intrapromoter interactions with the alpha4 and alpha5 NC1 domains. J Biol Chem. 2002 Oct 18; 277(42):40075-83.	PubMed
46.	Borza DB, Hudson BG. Of mice and men: murine models of anti-GBM antibody nephritis. Kidney Int. 2002 May; 61(5):1905-6.	PubMed
47.	Borza DB, Bondar O, Ninomiya Y, Sado Y, Naito I, Todd P, Hudson BG. The NC1 domain of collagen IV encodes a novel network composed of the alpha 1, alpha 2, alpha 5, and alpha 6 chains in smooth muscle basement membranes. J Biol Chem. 2001 Jul 27; 276(30):28532-40.	PubMed
48.	David M, Borza DB, Leinonen A, Belmont JM, Hudson BG. Hydrophobic amino acid residues are critical for the immunodominant epitope of the Goodpasture autoantigen. A molecular basis for the cryptic nature of the epitope. J Biol Chem. 2001 Mar 2; 276(9):6370-7.	PubMed
49.	Boutaud A, Borza DB, Bondar O, Gunwar S, Netzer KO, Singh N, Ninomiya Y, Sado Y, Noelken ME, Hudson BG. Type IV collagen of the glomerular basement membrane. Evidence that the chain specificity of network assembly is encoded by the noncollagenous NC1 domains. J Biol Chem. 2000 Sep 29; 275(39):30716-24.	PubMed
50.	Borza DB, Netzer KO, Leinonen A, Todd P, Cervera J, Saus J, Hudson BG. The goodpasture autoantigen. Identification of multiple cryptic epitopes on the NC1 domain of the alpha3(IV) collagen chain. J Biol Chem. 2000 Feb 25; 275(8):6030-7.	PubMed
51.	Netzer KO, Leinonen A, Boutaud A, Borza DB, Todd P, Gunwar S, Langeveld JP, Hudson BG. The goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17-31 and 127-141 of the NC1 domain. J Biol Chem. 1999 Apr 16; 274(16):11267-74.	PubMed
52.	Borza DB, Morgan WT. Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. J Biol Chem. 1998 Mar 6; 273(10):5493-9.	PubMed
53.	Borza DB, Morgan WT. Acceleration of plasminogen activation by tissue plasminogen activator on surface-bound histidine-proline-rich glycoprotein. J Biol Chem. 1997 Feb 28; 272(9):5718-26.	PubMed
54.	Borza DB, Tatum FM, Morgan WT. Domain structure and conformation of histidine-proline-rich glycoprotein. Biochemistry. 1996 Feb 13; 35(6):1925-34.	PubMed

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