Medical School or Training: M.D., Northwestern University Medical School, 2000
Residency: University of Michigan Health System, Pediatrics, MI, 2003
Fellowship: Pediatric Hematology/Oncology, University of Michigan Health System, 2006
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 which will be followed by targeted disruption using CRISPR and TALEN 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.
Weyand, AC and Shavit JA. Zebrafish as a model system for the study of hemostasis and thrombosis. Curr Opin Hematol, 21:418-22, 2014.
Liu Y, Kretz, CA, Maeder ML, Richter CE, Tsao P, Vo AH, Huarng, MC, Rode T, Hu Z, Mehra R, Olson ST, Joung JK, and Shavit JA. Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function, Blood, 124:142-50, 2014.
Vo A, Swaroop A, Liu Y, Norris ZG, and Shavit JA. Loss of fibrinogen in zebrafish results in symptoms consistent with human hypofibrinogenemia, PLOS One, 8:e74682, 2013.
Ghosh A, Vo A, Twiss BK, Kretz CA, Jozwiak MA, Montgomery RR, and Shavit JA. Characterization of zebrafish von Willebrand factor reveals conservation of domain structure, multimerization, and intracellular storage. Adv Hematol, 2012:1-9, 2012.
Chen X, Leto D, Xiao J, Goss J, Wang Q, Shavit JA, Xiong T, Yu G, Ginsburg D, Toomre D, Xu Z, and Saltiel AR. The function of the exocyst is regulated by effector phosphorylation. Nat. Cell Biol., 13:580-8, 2011.
Peters LL, Shavit JA, Lambert AJ, Tsaih S, Li Q, Su Z, Leduc MS, Paigen B, Churchill, GA, Ginsburg D, and Brugnara C. Sequence variation at multiple loci influences red cell hemoglobin concentration. Blood, 116:e139-49, 2010.
Shavit JA, Manichaikul, A, Lemmerhirt HL, Broman KW, and Ginsburg D. Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice. Blood, 114:5368-74, 2009.
Buchner DA, Su F, Yamaoka JS, Kamei M, Shavit JA, Barthel LK, McGee B, Amigo JD, Kim S, Hanosh AW, Jagadeeswaran P, Goldman D, Lawson ND, Raymond PA, Weinstein BM, Ginsburg D, and Lyons SE. pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci USA 104:13996-14001, 2007.