Person
Chan, Sherine
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Biography and Research Interest
Our mission is to understand how mitochondrial defects give rise to cellular dysfunction and disease. This is not an easy task, as the mitochondrion performs many essential functions, the most important being the production of most of the energy for the cell. Defects in any of the approximately 1,500 mitochondrial proteins can lead to pathological states such as neurodegeneration and cancer. In addition to genetic defects, mitochondrial dysfunction can arise from contact with many environmental agents and drug treatments. Mitochondria contain multiple copies of their own small, circular genome (mitochondrial DNA, mtDNA). Recently, investigators reported that 1 in 5 healthy humans harbor a pathogenic mtDNA mutation. Further complicating the understanding of mitochondrial diseases are issues related to mtDNA copy number in different tissues and different cellular states, levels of mtDNA mutations within cells (known as heteroplasmy), tissue differences in mitochondrial needs, and wide variability in disease presentation and onset of disease despite the same disease mutation.
We use several diverse in vitro and in vivo methods to analyze mitochondrial dysfunction. In particular, we are using the zebrafish as a model for mitochondrial diseases. There are no cures or effective long-term treatments for mitochondrial diseases. To fulfill our long-term goals of developing therapeutic treatments and new biomarkers for the early detection of mitochondrial disease, we are investigating pathways that are important in the development of mitochondrial disease, and the role of environmental and drug modifiers on mitochondrial function.
We use several diverse in vitro and in vivo methods to analyze mitochondrial dysfunction. In particular, we are using the zebrafish as a model for mitochondrial diseases. There are no cures or effective long-term treatments for mitochondrial diseases. To fulfill our long-term goals of developing therapeutic treatments and new biomarkers for the early detection of mitochondrial disease, we are investigating pathways that are important in the development of mitochondrial disease, and the role of environmental and drug modifiers on mitochondrial function.
Non-Zebrafish Publications
Bohovych I, Chan SSL, Khalimonchuk O. Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. 2015. Antioxidants and Redox Signaling, 145(1):108-17. PMCID: PMC4408963.
Whitaker RM, Stallons LJ, Kneff JE, Harmon JL, Rahn JJ, Arthur JM, Beeson CC, Chan SSL and Schnellmann RG. Urinary mitochondrial DNA predicts progression of renal dysfunction and mitochondrial disruption in acute kidney injury. Kidney International. 2015. In Press.
Zhang L*, Chan SSL*, Wolff D. Mitochondrial Disorders of DNA Polymerase γ Dysfunction: From Anatomic to Molecular Pathology Diagnosis. 2011. Archives of Pathology and Laboratory Medicine. * co-first authors. PMCID: PMC3158670.
Chan SSL, Copeland WC. Functional assessment of mutant mitochondrial DNA polymerase proteins involved in human disease. 2009. Methods in Molecular Biology, 554:59-72. PMCID: PMC2886993
Chan SSL, Naviaux RK, Basinger AA, Casas KA, Copeland WC. De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome. 2009. Mitochondrion, 9(5):340-345. PMCID: PMC2748142
Kasiviswanathan R, Longley MJ, Chan SSL, Copeland WC. Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mtDNA replication. 2009. Journal of Biological Chemistry, 284(29):19501-19510. PMCID: PMC2740576
Chan SSL, Copeland WC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. 2009. Biochimica et Biophysica Acta – Bioenergetics, 1787(5):312-319. PMCID: PMC2742478
Chan SSL, Santos JH, Meyer JN, Mandavilli BS, Cook Jr DL, McCash CL, Kissling G, Nyska A, Foley JF, van Houten B, Copeland WC, Walker VE, Witt, KL, Bishop JB. Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. 2007. Environmental and Molecular Mutagenesis, 48(3-4):190-200.
Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SSL, Green E, Haase CP, Keebaugh E, Long R, Ludaway T, Russ R, Steltzer J, Tioleco N, Santoianni R, Copeland WC. Mitochondrial DNA depletion, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. 2007. Laboratory Investigation, 87(4):318-325. PMCID: PMC1831462
Nguyen KV, Sharief FS, Chan SSL, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. 2006. Journal of Hepatology. 45(1):108-116.
Chan SSL, Longley MJ, Copeland WC. Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphism in mitochondrial disorders. 2006. Human Molecular Genetics, 15(23):3473-3483. PMCID: PMC1780027
Chan SSL, Longley MJ, Copeland WC. A common A467T mutation in POLG compromises catalytic efficiency and interaction with the accessory subunit in mitochondrial DNA polymerase. 2005. Journal of Biological Chemistry, 280(36):31341-31346.
Chan SSL, Longley MJ, Naviaux RK, Copeland WC. Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers Syndrome. 2005. DNA Repair, 4(12):1381-1389.
Chan SSL, Kent GN, Will RK. A sensitive assay for the measurement of serum chondroitin sulfate 3B3(-) epitope levels in human rheumatic diseases. Clinical and Experimental Rheumatology. 2001. 19(5):533-540.