gabriel-velez@uiowa.edu
Mentor: Vinit Mahajan, M.D./Ph.D.
Lab Room: 1257C CBRB
Lab Phone: 319-384-1700

Structure and function of calpain-5 in autosomal dominant neovascular inflammatory vitreoretinopathy

The eye is an immune-privileged site that is particularly prone to autoinflammatory uveitis. Most causes of uveitis are unknown, thereby delaying treatment and allowing ocular inflammation to progress unabated. Mutations in the cysteine protease calpain-5 (CAPN5) cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a rare form of nonsyndromic uveitis. ADNIV patients develop ocular inflammation, retinal degeneration and neovascularization, and intraocular fibrosis starting in the second decade of life, culminating in blindness in their fifties. ADNIV mutations lead to the production of an overactive protease. To date, there are no calpain inhibitors specific to calpain-5 and its structure and function are poorly understood. Determining the structure of calpain-5 is critical to developing precise therapies for ADNIV. The Mahajan lab utilizes a variety of structural, enzymatic, and proteomics techniques to uncover the structure and regulatory mechanisms of this poorly understood molecule.

Abe K, Cox A, Takamatsu N, Velez G, Laxer RM, Tse S, Mahajan VB, Bassuk AG, Fuchs H, Hrabě de Angelis M, Ferguson PJ. Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans. Proc Natl Acad Sci USA. 2019. In press.

Velez G, Yang J, Li AS, Tsang SH, Bassuk AG, Mahajan VB. Proteomic insight into the pathogenesis of CAPN5 vitreoretinopathy. Sci Rep. 2019; 9 (1):7608. PMID: 31110225.

Sancho-Pelluz J, Cui X, Lee W, Tsai YT, Hsuan W, Justus SE, Washington I, Hsu CW, Park KS, Koch S, Velez G, Bassuk AG, Mahajan VB, Lin CS, Tsang SH. Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation. Cell Mol Life Sci. 2019. In press. PMID: 30976840.

Tang PH*, Velez G*, Tsang SH, Bassuk AG, Mahajan VB. VCAN canonical splice site mutation is associated with vitreoretinal degeneration and disrupts an MMP proteolytic site. Invest Ophthalmol Vis Sci. 2019; 60(1):282-293. PMID: 30657523. * - co-first authors.

Jauregui R, Thomas AL, Liechty B, Velez G, Mahajan VB, Clark L, Tsang SH. SCAPER-associated non-syndromic autosomal recessive retinitis pigmentosa. Am J Med Genet A. 2019; 179(2):312-316. PMID: 30561111.

Almeida DR, Chin EK, Arjmand P, Velez G, Evans LP, Mahajan VB. Fibrin glue and internal limiting membrane abrasion for treatment of optic disc pit maculopathy. Ophthalmic Surg Lasers Imaging Retina. 2018; 49: e271-e277. PMID: 30566713.

Machlab DA*, Velez G*, Bassuk AG, Mahajan VB. ProSave: An application for restoring quantitative data to manipulated subsets of protein lists. Source Code Biol Med. 2018; 13: 3. * - co-first authors. PMID: 30459825.

Velez G, Tang PH, Cabral T, Cho GY, Machlab DA, Tsang SH, Bassuk AG, Mahajan VB. Personalized proteomics for precision health: identifying biomarkers of vitreoretinal disease. Transl Vis Sci Technol. 2018; 7(5): 12. PMID: 30271679.

Liu KY, Sengillo JD, Velez G, Jauregui R, Sakai LY, Maumenee IH, Bassuk AG, Mahajan VB, Tsang SH. Missense mutation in SLIT2 associated with myopia, anisometropia, connective tissue abnormalities, and obesity. Orphanet J Rare Dis. 2018; 13(1): 138. PMID: 30111362.

Wert KJ, Velez G, Cross MR, Wagner BA, Teoh-Fitzgerald ML, Buettner GR, McAnany J, Oliver A, Tsang SH, Harper MM, Domann FE, Bassuk AG, Mahajan VB. Extracellular superoxide dismutase 3 (SOD3) regulates oxidative stress at the vitreoretinal interface. Free Radic Biol Med. 2018; S0891-5849(18): 31114-6. PMID: 29940351.

Velez G, Bassuk AG, Schaefer KA, Brooks B, Gakhar L, Mahajan M, Kahn P, Tsang SH, Ferguson PJ, Mahajan VB. A novel de novo CAPN5 mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay. Cold Spring Harb Mol Case Stud. 2018 Feb 22. pii: mcs.a002519. doi:10.1101/mcs.a002519. [Epub ahead of print] PubMed PMID: 29472286.

Velez G, Machlab DA, Tang PH, Sun Y, Tsang SH, Bassuk AG, Mahajan VB. Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic- and oxidative stress-related diseases. PLoS One. 2018 Feb 21;13(2):e0193250. doi: 10.1371/journal.pone.0193250. eCollection 2018. PubMed PMID: 29466423; PubMed Central PMCID: PMC5821407.

Velez G, Bassuk AG, Colgan D, Tsang SH, Mahajan VB. Therapeutic drug repositioning using personalized proteomics of liquid biopsies. JCI Insight. 2017 Dec 21;2(24). pii: 97818. doi: 10.1172/jci.insight.97818. [Epub ahead of print] PubMed PMID: 29263305; PubMed Central PMCID: PMC5752263.

Roybal CN, Velez G, Toral MA, Tsang SH, Bassuk AG, Mahajan VB. Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target. Am J Ophthalmol. 2018 Feb;186:152-163. doi: 10.1016/j.ajo.2017.11.025. Epub 2017 Dec 13. PubMed PMID:29246578; PubMed Central PMCID: PMC5805631.

Velez G, Tsang SH, Tsai YT, Hsu CW, Gore A, Abdelhakim AH, Mahajan M, Silverman RH, Sparrow JR, Bassuk AG, Mahajan VB. Gene Therapy Restores Mfrp and Corrects Axial Eye Length. Sci Rep. 2017 Nov 23;7(1):16151. doi:10.1038/s41598-017-16275-8. PubMed PMID: 29170418; PubMed Central PMCID:PMC5701072.

Cabral T, Toral MA, Velez G, DiCarlo JE, Gore AM, Mahajan M, Tsang SH, Bassuk AG, Mahajan VB. Dissection of Human Retina and RPE-Choroid for Proteomic Analysis. J Vis Exp. 2017 Nov 12;(129). doi: 10.3791/56203. PubMed PMID:29155757.

Velez G, Roybal CN, Binkley E, Bassuk AG, Tsang SH, Mahajan VB. Proteomic Analysis of Elevated Intraocular Pressure with Retinal Detachment. Am J Ophthalmol Case Rep. 2017 Apr;5:107-110. doi: 10.1016/j.ajoc.2016.12.023. Epub 2017 Jan 3. PubMed PMID: 28825049; PubMed Central PMCID: PMC5560621.

Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, Erives A, Mahajan VB, Bassuk AG, Ferguson PJ. Correction: Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS One. 2017 Jul 7;12(7):e0181222. doi: 10.1371/journal.pone.0181222. eCollection 2017. PubMed PMID: 28686717; PubMed Central PMCID: PMC5501673.

Toral MA, Velez G, Boudreault K, Schaefer KA, Xu Y, Saffra N, Bassuk AG, Tsang SH, Mahajan VB. Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia. Mol Genet Genomic Med. 2017 Feb 26;5(3):202-209. doi:10.1002/mgg3.266. eCollection 2017 May. PubMed PMID: 28546991; PubMed Central PMCID: PMC5441399.

Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, Erives A, Mahajan VB, Bassuk AG, Ferguson PJ. Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS One. 2017 Mar 16;12(3):e0169687. doi: 10.1371/journal.pone.0169687. eCollection 2017. Erratum in: PLoS One. 2017 Jul 7;12 (7):e0181222. PubMed PMID: 28301468; PubMed Central PMCID: PMC5354242.

Chin EK, Almeida DRP, Velez G, Xu K, Peraire M, Corbella M, Elshatory YM, Kwon YH, Gehrs KM, Boldt HC, Sohn EH, Russell SR, Folk JC, Mahajan VB. OCULAR HYPERTENSION AFTER INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT. Retina. 2017 Jul;37(7):1345-1351. doi: 10.1097/IAE.0000000000001364. PubMed PMID: 27806001; PubMed Central PMCID: PMC5411345.

Gakhar L, Bassuk AG, Velez G, Khan S, Yang J, Tsang SH, Mahajan VB. Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains. J Struct Biol. 2016 Dec;196(3):309-318. doi:10.1016/j.jsb.2016.07.017. Epub 2016 Jul 27. PubMed PMID: 27474374; PubMed Central PMCID: PMC5118095.

Moshfegh Y, Velez G, Li Y, Bassuk AG, Mahajan VB, Tsang SH. BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE. Hum Mol Genet. 2016 Jul 1;25(13):2672-2680. Epub 2016 May 18. PubMed PMID:27193166; PubMed Central PMCID: PMC5181636.

Schaefer KA, Toral MA, Velez G, Cox AJ, Baker SA, Borcherding NC, Colgan DF, Bondada V, Mashburn CB, Yu CG, Geddes JW, Tsang SH, Bassuk AG, Mahajan VB. Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses. Invest Ophthalmol Vis Sci. 2016 May 1;57(6):2509-21. doi: 10.1167/iovs.15-18680. PubMed PMID: 27152965; PubMed Central PMCID: PMC4868102.

Velez G, Roybal CN, Colgan D, Tsang SH, Bassuk AG, Mahajan VB. Precision Medicine: Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease. JAMA Ophthalmol. 2016 Apr;134(4):444-8. doi:10.1001/jamaophthalmol.2015.5934. PubMed PMID: 26848019; PubMed Central PMCID:PMC4833518.