ZFIN ID: ZDB-LAB-090807-1
Shavit Lab
PI/Director: Shavit, Jordan
Contact Person: Shavit, Jordan
Email: jshavit@umich.edu
URL: http://www.shavitlab.org
Address: Department of Pediatrics University of Michigan 8301 MSRB III 1500 E. Medical Center Drive Ann Arbor, MI 48109-5646
Country: United States
Phone: 734-647-4365
Fax: 734-936-2888
Line Designation: mi

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In the Shavit laboratory we perform “clinically directed basic research” in the field of hemostatic and thrombotic disorders. Patients with deficiencies of particular blood coagulation factors are often labeled with bleeding or clotting disorders, yet often have no phenotype. On the other hand there are patients with phenotypes out of proportion to their laboratory clotting factor profile. Thus we are often unable to predict an individual patient's risk with any useful degree of accuracy. Our goal is the identification of genes that modify blood clotting factors and their phenotypic expression. Knowledge of such modifier genes will improve diagnosis and classification of blood coagulation disorders, identify potential targets for therapy, and further our understanding of the underlying biology of hemostasis and thrombosis. In order to achieve these goals, we are developing zebrafish models of human blood clotting disorders. To date there has been relatively little characterization of the blood coagulation system in zebrafish, and we are currently characterizing the expression pattern of various clotting factors and performing targeted disruption using mutagenesis with zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and CRISPR/Cas (clustered regularly interspaced short palindromic repeats) endoribonuclease technology. Sensitized ethylnitrosourea (ENU) mutagenesis and high throughput chemical suppressor screens will be performed on mutants with bleeding and thrombotic phenotypes. This strategy will identify genetic and chemical modifiers of clotting phenotypes, and once characterized they will be examined in murine models and patient populations.

We are also enhancing our previous work mapping quantitative trait loci (QTL) for blood clotting factors in the mouse by performing similar studies in zebrafish. Mouse QTL mapping involves generating pedigrees of hundreds of mice at great expense. Since zebrafish pairs can produce hundreds of embryos with each mating, this work becomes more rapid and significantly less expensive. We are developing techniques to measure blood clotting factors in zebrafish which will be followed by mapping of QTLs. After positional cloning and characterization of the underlying genes, we will analyze these in murine models and patient populations.

Azhwar, Raghunath Post-Doc Daniel, Jeffrey G. Post-Doc Weyand, Angela Post-Doc
Yaman, Murat Post-Doc Yu, Xinge Post-Doc Emly, Sylvia Graduate Student
Richter, Catherine Research Staff Ferguson, Allison Technical Staff Keesling, Ashley Technical Staff
Pontius, Maxine Technical Staff Zhao, Yakun Technical Staff Weng, Maxwell

Bragazzi Cunha, J., Elenbaas, J.S., Maitra, D., Kuo, N., Azuero-Dajud, R., Ferguson, A.C., Griffin, M.S., Lentz, S.I., Shavit, J.A., Omary, M.B. (2021) Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models. Scientific Reports. 11:9601
Freire, C., Fish, R.J., Vilar, R., Di Sanza, C., Grzegorski, S.J., Richter, C.E., Shavit, J.A., Neerman-Arbez, M. (2020) A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen AαE in early hemostasis. Blood advances. 4:5480-5491
Bando, H., Gergics, P., Bohnsack, B.L., Toolan, K.P., Richter, C.E., Shavit, J.A., Camper, S.A. (2020) otx2b mutant zebrafish have pituitary, eye and mandible defects that model mammalian disease. Human molecular genetics. 29(10):1648-1657
Tharmalingam, B., Mathivanan, M., Mani, K.S., Kaminsky, W., Raghunath, A., Jothi, M., Perumal, E., Murugesapandian, B. (2020) Selective detection of pyrophosphate anion by zinc ensemble of C3-symmetric triaminoguanidine-pyrrole conjugate and its biosensing applications. Analytica chimica acta. 1103:192-201
Grzegorski, S.J., Hu, Z., Liu, Y., Yu, X., Ferguson, A.C., Madarati, H., Friedmann, A.P., Reyon, D., Kim, P.Y., Kretz, C.A., Joung, J.K., Shavit, J.A. (2020) Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish. Scientific Reports. 10:4049
Balasubramanian, S., Raghunath, A., Perumal, E. (2019) Role of epigenetics in zebrafish development. Gene. 718:144049
Mani, R., Balasubramanian, S., Raghunath, A., Perumal, E. (2019) Chronic exposure to copper oxide nanoparticles causes muscle toxicity in adult zebrafish. Environmental science and pollution research international. 27(22):27358-27369
Weyand, A.C., Grzegorski, S.J., Rost, M.S., Lavik, K.I., Ferguson, A.C., Menegatti, M., Richter, C.E., Asselta, R., Duga, S., Peyvandi, F., Shavit, J.A. (2019) Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis. Blood advances. 3:1670-1680
Thiessen, K.D., Grzegorski, S.J., Chin, Y., Higuchi, L., Wilkinson, C.J., Shavit, J.A., Kramer, K.L. (2019) Zebrafish otolith biomineralization requires polyketide synthase. Mechanisms of Development. 157:1-9
Hortle, E., Johnson, K.E., Johansen, M.D., Nguyen, T., Shavit, J.A., Britton, W.J., Tobin, D.M., Oehlers, S.H. (2019) Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish. The Journal of infectious diseases. 220(3):524-534
Raghunath, A., Nagarajan, R., Sundarraj, K., Palanisamy, K., Perumal, E. (2019) Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish. Basic & Clinical Pharmacology & Toxicology. 125(3):259-270
Hu, Z., Lavik, K.I., Liu, Y., Vo, A.H., Richter, C.E., Di Paola, J., Shavit, J.A. (2019) Loss of fibrinogen in zebrafish results in an asymptomatic embryonic hemostatic defect and synthetic lethality with thrombocytopenia. Journal of thrombosis and haemostasis : JTH. 17(4):607-617
Maitra, D., Bragazzi Cunha, J., Elenbaas, J.S., Bonkovsky, H.L., Shavit, J.A., Omary, M.B. (2019) Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury. Cellular and molecular gastroenterology and hepatology. 8:535-548
Rost, M.S., Shestopalov, I., Liu, Y., Vo, A.H., Richter, C.E., Emly, S.M., Barrett, F.G., Stachura, D.L., Holinstat, M., Zon, L.I., Shavit, J.A. (2018) Nfe2 is dispensable for early but required for adult thrombocyte formation and function in zebrafish. Blood advances. 2:3418-3427
Raghunath, A., Nagarajan, R., Sundarraj, K., Panneerselvam, L., Perumal, E. (2018) Genome-wide identification and analysis of Nrf2 binding sites - Antioxidant response elements in zebrafish. Toxicology and applied pharmacology. 360:236-248
Khoriaty, R., Hesketh, G.G., Bernard, A., Weyand, A.C., Mellacheruvu, D., Zhu, G., Hoenerhoff, M.J., McGee, B., Everett, L., Adams, E.J., Zhang, B., Saunders, T.L., Nesvizhskii, A.I., Klionsky, D.J., Shavit, J.A., Gingras, A.C., Ginsburg, D. (2018) Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo. Proceedings of the National Academy of Sciences of the United States of America. 115(33):E7748-E7757
Raghunath, A., Perumal, E. (2018) Analysis of Lethality and Malformations During Zebrafish (Danio rerio) Development. Methods in molecular biology (Clifton, N.J.). 1797:337-363
Hu, Z., Liu, Y., Huarng, M.C., Menegatti, M., Reyon, D., Rost, M.S., Norris, Z.G., Richter, C.E., Stapleton, A.N., Chi, N.C., Peyvandi, F., Joung, J.K., Shavit, J.A. (2017) Genome editing of factor X in zebrafish reveals unexpected tolerance of severe defects in the common pathway. Blood. 130(5):666-676
Williams, L.M., Lago, B.A., McArthur, A.G., Raphenya, A.R., Pray, N., Saleem, N., Salas, S., Paulson, K., Mangar, R.S., Liu, Y., Vo, A.H., Shavit, J.A. (2016) The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development. Aquatic toxicology (Amsterdam, Netherlands). 180:141-154
Kc, R., Srivastava, A., Wilkowski, J.M., Richter, C.E., Shavit, J.A., Burke, D.T., Bielas, S.L. (2016) Detection of nucleotide-specific CRISPR/Cas9 modified alleles using multiplex ligation detection. Scientific Reports. 6:32048
Elenbaas, J.S., Maitra, D., Liu, Y., Lentz, S.I., Nelson, B., Hoenerhoff, M.J., Shavit, J.A., Omary, M.B. (2016) A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 30(5):1798-810
Ganesan, S., Anaimalai Thirumurthi, N., Raghunath, A., Vijayakumar, S., Perumal, E. (2016) Acute and sub-lethal exposure to copper oxide nanoparticles causes oxidative stress and teratogenicity in zebrafish embryos. Journal of applied toxicology : JAT. 36(4):554-67
Rost, M.S., Grzegorski, S.J., Shavit, J.A. (2016) Quantitative methods for studying hemostasis in zebrafish larvae. Methods in cell biology. 134:377-89
Yu, X., Li, Y.V. (2016) Zebrafish (Danio rerio) Developed as an Alternative Animal Model for Focal Ischemic Stroke. Acta neurochirurgica. Supplement. 121:115-119
Huarng, M.C., Shavit, J.A. (2015) Simple and Rapid Quantification of Thrombocytes in Zebrafish Larvae. Zebrafish. 12(3):238-42
Kretz, C.A., Weyand, A.C., Shavit, J.A. (2015) Modeling Disorders of Blood Coagulation in the Zebrafish. Current pathobiology reports. 3:155-161
Ghosh, A., Vo, A., Twiss, B.K., Kretz, C.A., Jozwiak, M.A., Montgomery, R.R., Shavit, J.A. (2015) Corrigendum to "Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage". Advances in hematology. 2015:526854
Weyand, A.C., Shavit, J.A. (2014) Zebrafish as a model system for the study of hemostasis and thrombosis. Current opinion in hematology. 21(5):418-22
Liu, Y., Kretz, C.A., Maeder, M.L., Richter, C.E., Tsao, P., Vo, A.H., Huarng, M.C., Rode, T., Hu, Z., Mehra, R., Olson, S.T., Joung, J.K., and Shavit, J.A. (2014) Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function. Blood. 124(1):142-50
Raeker, M.Ö., Shavit, J.A., Dowling, J.J., Michele, D.E., and Russell. M.W. (2014) Membrane-myofibril cross-talk in myofibrillogenesis and in muscular dystrophy pathogenesis: lessons from the zebrafish. Frontiers in Physiology. 5:14
Vo, A.H., Swaroop, A., Liu, Y., Norris, Z.G., and Shavit, J.A. (2013) Loss of fibrinogen in zebrafish results in symptoms consistent with human hypofibrinogenemia. PLoS One. 8(9):e74682
Ghosh, A., Vo, A., Twiss, B.K., Kretz, C.A., Jozwiak, M.A., Montgomery, R.R., and Shavit, J.A. (2012) Characterization of zebrafish von Willebrand factor reveals conservation of domain structure, multimerization, and intracellular storage. Advances in hematology. 2012:214209
Chen, X.W., Leto, D., Xiao, J., Goss, J., Wang, Q., Shavit, J.A., Xiong, T., Yu, G., Ginsburg, D., Toomre, D., Xu, Z., and Saltiel, A.R. (2011) Exocyst function regulated by effector phosphorylation. Nature cell biology. 13(5):580-588
Su, F., Juarez, M.A., Cooke, C.L., LaPointe, L., Shavit, J.A., Yamaoka, J.S., and Lyons, S.E. (2007) Differential Regulation of Primitive Myelopoiesis in the Zebrafish by Spi-1/Pu.1 and C/ebp1. Zebrafish. 4(3):187-199
Buchner, D.A., Su, F., Yamaoka, J.S., Kamei, M., Shavit, J.A., Barthel, L.K., McGee, B., Amigo, J.D., Kim, S., Hanosh, A.W., Jagadeeswaran, P., Goldman, D., Lawson, N.D., Raymond, P.A., Weinstein, B.M., Ginsburg, D., and Lyons, S.E. (2007) pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 104(35):13996-140001