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Training Grant-
Biology of Aging
:

Ying Ge

Ying Ge

PhD, Cornell University
Associate Professor, Dept. of Cell & Regenerative Biology
ge2@wisc.edu
crb.wisc.edu/yinglab/
www.crb.wisc.edu/faculty/Ge.asp


A Systems Biology Approach for Understanding Cardiovascular Aging

I have established a trans-disciplinary research program that cuts across the traditional boundaries of chemistry, biology, and medicine. We aim to understand the molecular and cellular mechanisms underlying cardiovascular diseases via novel systems biology approaches featuring cutting-edge ultra high-resolution mass spectrometry (MS)-based disease proteomics and metabolomics in conjunction with functional studies.

Research Overview chart

Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. In the elderly, cardiovascular disease is commonly associated with complications and poor clinical outcomes. Consequently, cardiovascular disease is predominant in the aging population, with approximately 85% of all death in the elderly in US attributable to cardiovascular disease. Despite recent therapeutic advances, cardiovascular disease remains the greatest risk in the elderly.

Transformative insights from a holistic approach at the systems level have great potential to elucidate disease mechanisms and to develop new therapeutic treatments in cardiovascular disease. Proteins and metabolites are important molecular entities of the cell downstream of genes. Hence in the post genomic era, proteomics and metabolomics (the large-scale global analysis of proteins and metabolites in a cell, organism, tissue, and biofluid), are essential for deciphering how molecules interact as a system and for understanding the functions of cellular systems in health and disease. Herein, we employ novel systems biology approaches featuring ultra high-resolution MS-based top-down disease proteomics and metabolomics platforms. We globally identify, characterize, and quantify intact proteins and metabolites extracted from tissues/cells/biofluids and reveal all changes in the proteome and metabolome in response to extrinsic and intrinsic stresses in a label-free, automated, and high-throughput fashion. We then integrate the proteomic/metabolomic analyses with biochemical and physiological functional assays to study cardiovascular diseases and the changes related to aging. Success in my proposed research will advance our understanding of the molecular basis of diseases and foster the development of new strategies for early diagnosis, prevention and better treatment of cardiovascular diseases especially in the elderly.



Representative Publications
Chen, B., Peng, Y., Valeja, S. G., Xiu, L., Alpert, A. J., & Ge, Y. (2016). Online hydrophobic interaction chromatographymass spectrometry for top-down proteomics. Analytical Chemistry, 88(3), 1885-1891.
View publication via DOI: DOI:10.1021/acs.analchem.5b04285

Cai, W., Guner, H., Gregorich, Z. R., Chen, A. J., Ayaz-Guner, S., Peng, Y., Valeja, S. G., Liu, X., & Ge, Y. (2016). Mash suite pro: A comprehensive software tool for top-down proteomics. Molecular and Cellular Proteomics, 15(2), 703-714.
View publication via DOI: DOI:10.1074/mcp.O115.054387

Yu, D., Peng, Y., Ayaz-Guner, S., Gregorich, Z. R., & Ge, Y. (2016). Comprehensive characterization of amp-activated protein kinase catalytic domain by top-down mass spectrometry. Journal of the American Society for Mass Spectrometry, 27(2), 220-232.
View publication via DOI: DOI:10.1007/s13361-015-1286-8

Gregorich, Z. R., Cai, W., Jin, Y., Wei, L., Chen, A. J., McKiernane, S. H., Aiken, J. M., Moss, R. L., Diffee, G. M., & Ge, Y. (2016). Top-down targeted proteomics reveals decrease in myosin regulatory light chain phosphorylation that contributes to sarcopenic muscle dysfunction. Journal of Proteome Research, 15 (8), 2706-2716.
View publication via DOI: DOI:10.1021/acs.jproteome.6b00244

Hwang, L., Ayaz-Guner, S., Cai, W., Gregorich, Z.R., Jin, S., & Ge, Y. (2015). Specific enrichment of phosphoproteins using functionalized multivalent nanoparticles. Journal of the American Chemical Society, Epub ahead of print.
View publication via DOI: DOI:10.1021/ja511833y

Chang, Y., Gregorich Z.R., Chen, A. J., Hwang, L., Guner, H., Yu, D., Zhang, J., & Ge, Y. (2015). New mass spectrometry-compatible degradable surfactant for tissue proteomics. Journal of Proteome Research, Epub ahead of print.
View publication via DOI: DOI:10.1021/pr5012679

Chen, Y., Sumandea, M.P., Larsson, L., Moss, R.L., & Ge, Y. (2015). Dissecting human skeletal muscle troponin proteoforms by top-down mass spectrometry. Journal Muscle Research and Cell Motility, Epub ahead of print..
View publication via DOI: DOI:10.1007/s10974-015-9404-6

Gregorich, Z. R., Peng, Y., Lane, N. M., Wolff, J. J., Wang, S., Guo, W., Guner, H., Doop, J., Hacker, T. A., & Ge, Y. (2015). Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry. Journal of Molecular and Cellular Cardiology, 87, 102-112.
View publication via DOI: DOI:10.1016/j.yjmcc.2015.08.007

Chen, Y. C., Ayaz-Guner, S., Peng, Y., Lane, N. M., Locher, M. R., Kohmoto, T., Larsson, L., Moss, R. L., & Ge, Y. (2015). Effective top-down LC/MS+ method for assessing actin isoforms as a potential cardiac disease marker. Analytical Chemistry, 87(16), 8399-8406.
View publication via DOI: DOI:10.1021/acs.analchem.5b01745

Chang, Y. H., Ye, L., Cai, W., Lee, Y., Guner, H., Lee, Y., Kamp, T. J., Zhang, J., & Ge, Y. (2015). Quantitative Proteomics Reveals Differential Regulation of Protein Expression in Recipient Myocardium after Trilineage Cardiovascular Cell Transplantation. Proteomics, 15, 2560-2567.
View publication via DOI: DOI:10.1002/pmic.201500131

Valeja, S. G.; Xiu, L.; Gregorich, Z. R.; Guner, H.; Jin, S., & Ge, Y. (2015). Three dimensional liquid chromatography coupling ion exchange chromatography/hydrophobic interaction chromatography/reverse phase chromatography for effective protein separation in top-down proteomics. Analytical Chemistry, 87(10), 5363-71.
View publication via DOI: DOI:10.1021/acs.analchem.5b00657

Hwang, L., Ayaz-Guner, S., Gregorich, Z. R., Cai, W., Valeja, S. G., Jin, S., & Ge, Y. (2015). Specific enrichment of phosphoproteins using functionalized multivalent nanoparticles. Journal of the American Chemical Society, 137(7), 2432-2435.
View publication via DOI: DOI:10.1021/ja511833y

Cheng, S., Zhu, P., Guo, H-M., Solis, R. S., Wang, Y., Yina, M., . . . Ge, Y., . . . Li, J. (2014). Alpha1 catalytic subunit of AMPK modulates contractile function of cardiomyocytes through phosphorylation of troponin I. Life Sciences, 98(2), 75-82.
View publication via DOI: DOI:10.1016/j.lfs.2014.01.006

Guner, H., Close, P. L., Cai, W., Zhang, H., Peng, Y., Gregorich, Z. R., & Ge, Y. (2014). Mash suite: A user-friendly and versatile software interface for high-resolution mass spectrometry data interpretation and visualization. Journal of the American Society for Mass Spectrometry, 25(3) 464-470.
View publication via DOI: DOI:10.1007/s13361-013-0789-4

Ye, L., Chang, Y.H., Xiong, Q., Zhang, P., Somasundaram, P., Lepley, M., Swingen, C., Su, L., Wendel, J.S., Guo, J., Jang, A., Rosenbush, D., Zhang, L., Greder, L., Dutton, J,R., Zhang, J., Kamp, T.J., Kaufman, D.S., Ge, Y., & Zhang, J. (2014). Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Dissecting human skeletal muscle troponin proteoforms by top-down mass spectrometry.
View publication via DOI: DOI:10.1016/j.stem.2014.11.009

Peng, Y., Gregorich, Z.R., Valeja, S.G., Zhang, H., Cai, W., Chen, Y., Guner, H., Chen, A.J., Schwahn, D.J., Hacker, T.A., Liu, X., & Ge, Y. (2014). Top-down proteomics reveals concerted reductions in myofilament and Z-disc protein phosphorylation after acute myocardial infarction. Molecular and Cellular Proteomics, 13(10), 2752-2764.
View publication via DOI: DOI:10.1074/mcp.M114.040675

Xiu, L., Valeja, S.G., Alpert, A.J., Jin, S., & Ge, Y. (2014). Effective protein separation by coupling hydrophobic interaction and reverse phase chromatography for top-down proteomics. Analytical Chemistry, 86(15), 7899-7906.
View publication via DOI: DOI:10.1021/ac501836k

Valkevich, E. M., Sanchez, N., Ge, Y., & Strieter, E. R. (2014). Middle-down mass spectrometry enables characterization of branched ubiquitin chains. Biochemistry, 53, 4979-4989.
View publication via DOI: DOI:10.1021/bi5006305

Peng, Y., Ayaz-Guner, S., Yu, D., & Ge, Y. (2014). Top-down mass spectrometry of cardiac myofilament proteins in health and disease. Proteomics Clin. Appl, 8(7-8), 554-568.
View publication via DOI: DOI:10.1002/prca.201400043

Gregorich, Z.R., & Ge, Y. (2014). Top-down proteomics in health and disease: challenges and opportunities. Proteomics, 14(10), 1195-1210.
View publication via DOI: DOI:10.1002/pmic.201300432

Gregorich, Z.R., Chang, Y.H., Ge, Y. (2014). Proteomics in heart failure: top-down or bottom-up? Pflugers Archive, European Journal of Physiology, 466(6), 1199-1209.
View publication via DOI: DOI:10.1007/s00424-014-1471-9

Witayavanitkul, N., Sarkey, J., Mou, Y.A., Kuster, D.W.D., Khairallah, R.J., Govindan, S., Chen, X., Ge, Y., Rajan, S., Wieczorek, D.F., Irving, T., de Tombe, P.P., & Sadayappan, S. (2014). Myocardial infarction-induced N-terminal fragment of cMyBP-C impairs myofilament function in human left ventricular myofibrils. Biophysical Journal, 106(2), 8818-8827.
View publication via DOI: DOI:10.1016/j.bpj.2013.11.1977

Chen, S., Zhu, P., Guo, H., Wang, Y., Ma, Y., Wang, J., Gao, J., Chen, J., Ge, Y., Zhuang, J., & Li, J. (2014). A-1 catalytic subunit of AMPK modulates contractile function of cardiomyocytes through phosphorylation of troponin. Life Sciences, 98, 75-82.
View publication via DOI: DOI:10.1016/j.lfs.2014.01.006

Guy, M.J., Chen, Y.. Clinton, L., Zhang, H., Zhang, J., Dong, X., ...Ge, Y (2013). The impact of antibody selection on the detection of cardiac troponin I. Clinica Chimica Acta, 420, 82-88.
View publication via DOI: DOI:10.1016/j.cca.2012.10.034

Ge, Y., & Moss, R.L. (2012). Nitroxyl, redox switches, cardiac myofilaments, and heart failure: A prequel to novel therapeutics? Circulation Research, 111(8), 954-956.
View publication via DOI: DOI:10.1161/CIRCRESAHA.112.278416

Dong, X., Sumandea, C.A., Chen, Y., Garcia-Cazarin, M.L., Zhang, J., Balke, C.M., Sumandea, M.P., & Ge, Y. (2012). Augmented phosphorylation of cardiac troponin I in hypertensive heart failure. Journal of Biological Chemistry, 287(2), 848-857.
View publication via DOI: DOI:10.1074/jbc.M111.293258

Zhang, J., Guy, J.M., Norman, H.A., Chen, Y., Dong, X., Wang, S.,... Ge, Y (2011). Top-Down quantitative proteomics identified phosphorylation of cardiac troponin I as a candidate biomarker for chronic heart failure. Journal of Proteome Research, 10(9), 4054-4065.
View publication via DOI: DOI:10.1021/pr200258m

Zhang, J., Zhang, H., Ayaz-Guner, S., Chen, Y., Dong, X., Xu, Q., & Ge, Y. (2011). Phosphorylation, but not alternative splicing or proteolytic degradation, is conserved in human and mouse cardiac troponin T. Biochemistry, 50(27), 6081-6092.
View publication via DOI: DOI:10.1021/bi2006256`

Sancho Solis, R., Ge, Y., & Walker, J.W. (2011). A preferred AMPK phosphorylation site in the inhibitory loop of cardiac and skeletal troponin I. Protein Science, 20(5), 894-907.
View publication via DOI: DOI:10.1002/pro.623

Zhang, J., Dong, X., Hacker, T.A., & Ge, Y. (2010). Deciphering modifications in swine cardiac troponin I by top-down high-resolution tandem mass spectrometry. Journal of the American Society for Mass Spectrometry, 21(6), 940-948.
View publication via DOI: DOI:10.1016/j.jasms.2010.02.005

Ayaz-Guner, S., Zhang, J., Li, L., Walker, J.W., & Ge, Y. (2009). In vivo phosphorylation site mapping in mouse cardiac troponin I by high resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated. Biochemistry, 48(34), 8161-8170.
View publication via DOI: DOI:10.1021/bi900739f

Ge, Y., Rybakova, I., Xu, Q., & Moss, R.L. (2009). Top-down high resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state. Proceedings of the National Academy of Sciences of the United States of America,106(31), 12658-12663.
View publication via DOI: DOI:10.1073/pnas.0813369106

Zabrouskov, V., Ge, Y., Schwartz, J., & Walker, J.W. (2008). Unraveling molecular complexity of phosphorylated human cardiac troponin I by top down electron capture dissociation/electron transfer dissociation mass spectrometry. Molecular & Cellular Proteomics, 7(10), 1838-1849.
View publication via DOI: DOI:10.1074/mcp.M700524-MCP200

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