Ye Tao, Ph.D.
2121 W. Holcombe Blvd
Houston, TX 77030
Education and Training
University of Texas Health Science Center at Houston
Ph.D., Genes and Development, 2007
Chinese Academy of Sciences, China
M.S., Developmental Biology, 2001
Jilin University, China
B.S., Biochemistry, 1994
Children with sickle cell anemia (SCA) have a greatly increased risk of developing stroke compared to the general pediatric population. Up to 11% of SCA patients will suffer a stroke before 20 years of age. Previous sibling-pair analyses of children with SCA have demonstrated that there are genetic modifiers of cerebrovascular disease development, other than just the SCA gene mutation. By utilizing whole exome sequencing (WES) techniques, we have identified a number of missense gene variants that are highly associated with the risk of stroke in children with SCA (p<1X10-4). In particular, two GOLGB1 gene mutations, Y1212C and T911S, were identified and verified in our study as being significantly associated with decreased risk of stroke. GOLGB1 encodes a conserved Golgi membrane protein which is essential for the cargo transportation of the Golgi, and thus is important for normal transportation and secretion of macromolecules in the cell. From our WES results, we hypothesize that the GOLGB1 Y1212C and T911S mutations reduce the risk of stroke in children with SCA. To elucidate how these mutations in GOLGB1 might be protective against stroke, we are currently performing a serial of functional studies in vitro. We have generated individual lentivirus expression constructs encoding wild-type and mutant (Y1212C) GOLGB1 proteins and measured the effect of each mutation on GOLGB1 function by examining the morphology of Golgi and using intracellular protein transportation assays. We also knocked down endogenous GOLGB1 with small interfering RNA (siRNA) in several different cell lines. We have also confirmed by live cell imaging that we can monitor and measure protein transportation through the Golgi using a fluorescently tagged vesicular stomatitus virus G protein (VSVG-EGFP) reporter. Both over-expression and siRNA knockdown of GOLGB1 experiments have shown that there are morphologic changes in the Golgi apparatus and a dramatic decrease in Golgi transportation indicating the Y1212C mutation is crucial for maintain GOLGI morphology and cargo transportation function.
We are slo setting up the initial experimental conditions to investigate the effect of the GOLGB1 mutations in an in vitro model of stroke. We will expose multiple neuronal and brain endothelial cell lines to various oxygen-glucose deprivation (OGD) conditions to mimic ischemic stroke conditions in vitro. A hypoxia chamber will be used to generate the OGD conditions and we will evaluate cell survival and cell death after OGD treatment using: (i) measurement of mitochondrial reduction of XTT and lactate dehydrogenase release; (ii) flow cytometry analyses to determine percentage of cell death/apoptosis induced by OGD. Again using siRNA knockdown of endogenous GOLGB1 and rescue by transfection with lentivirus that express wild-type, Y1212C, and T911S mutant GOLGB1, we will determine whether there is direct effect of the GOLGB1 mutations that is protective against ischemic stroke.
Our study will not only elucidate the effect of GOLGB1 as a potential genetic modifier of stroke development, but also may improve our understanding of the molecular mechanisms that cause cerebrovascular disease in children with SCA.
Tao Y, Zhang M, Li L, Bai Y, Zhou Y, Moon AM, Kaminski HJ, Martin JF. Pitx2, an atrial fibrillation predisposition gene, stabilizes the postnatal intercalated disc Circ Cardiovasc Genet. 7(1):23-32 (2014).
Wang J, Bai Y, Li N, Ye W, Zhang M, Greene SB, Tao Y, Chen Y, Wehrens XH, Martin JF. Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation. Proc Natl Acad Sci U S A. 111(25):9181-6 (2014).
Tao Y, Duan X, Patrick DM, Ivey KN, Martin JF, Srivastava D, Olson EN, Schwartz RJ. miR-451 regulates the specification of multiple cell lineages during embryonic stem cell differentiation (manuscript).
Zheng G, Tao Y, Yu W, Schwartz RJ. SRF dependent miR-210 silencing of the Sonic hedgehog signaling pathway during cardiopoesis. Stem Cell. 31(10):2279-85 (2013).
Patrick DM, Zhang CC, Tao Y, Yao H, Qi X, Schwartz RJ, Jun-Shen Huang L, Olson EN. Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta. Genes & Development. 24(15):1614-9 (2010).
Wang J, Greene SB, Bonilla-Claudio M, Tao Y, Zhang J, Bai Y, Huang Z, Black BL, Wang F, Martin JF. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Developmental Cell, 19(6):903-12 (2010).
Tao Y, Schulz RA. Second chromosome genes required for heart development in Drosophila melanogaster. Genesis, 45(10):607-17 (2007).
Tao Y, Wang J, Tokusumi T, Gajewski KM, Schulz RA. Requirement of the LIM homeodomain transcription factor Tailup for normal heart and hematopoietic organ formation in Drosophila. Molecular and Cellular Biology, 27(11): 3962-9 (2007).
Tao Y, Schulz RA. Heart development in Drosophila. Seminars in Cell and Developmental Biology, 18 (1): 3-15 (2007).
Wang J, Tao Y, Reim I, Gajewski KM, Frasch M, Schulz RA. . Expression, regulation, and requirement of the Toll transmembrane protein during dorsal vessel formation in Drosophila melanogaster. Molecular and cellular Biology, 25 (10): 4200-4210 (2005).
Tao Y, Zhang J. The relationship between chicken anemia virus VP3 protein sequence and its nuclear localization. Progress in Biochemistry and Biophysics, 29(1): 100-104 (2002).
Tao Y, Zhang J. Apoptin - A protein that can specially induce apoptosis in tumorigenic cells. Progress in Biochemistry and Biophysics, 28(5): 631-634 (2001).