1993 B.A. Northwestern University (Xi’an China) 1998 PhD Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou,
China
Post-doctoral training
1998-2000 Shanghai Institute of Biochemistry, Chinese Academy of Sciences, Shanghai,
China 2000-2003 Case Western Reserve University, Cleveland, Ohio
Awards and Honors
• NEI ARVO Travel Grant Award, Fort Lauderdale, US, 2006. • Travel Fellowship Award for 9th International Symposium on the Maillard Reaction,
Munich, Germany, 2007. • Travel Fellowship Awards for 18th International Society of Eye Research, Beijing,
China, 2008. • Travel Fellowship Award for 10th International Symposium on the Maillard Reaction,
Cairns, Australian, 2009 • Travel Fellowship Award for International Conference on the Lens, Kona, Hawaii,
2015
Research Goal
We study the role of reactive oxygen species (ROS) in aging and age-related disease,
i.e., age-related nuclear cataract (ARNC) and Alzheimer’s disease (AD). We also use
in vitro and in vivo model systems to study posterior capsule opacification (PCO),
a common post cataract surgery complication.
Current Research
Mechanisms and consequences of impaired glutathione homeostasis in the aging lens.
Age-related cataracts (ARC) are the leading cause of blindness worldwide, and with
an estimated 20 million affected in at least one eye in people over 40 years in the
United States; it is expected to reach a stunning number of 30 million in 2020. Oxidation
has been documented as the major risk factor in age-related cataract formation. Glutathione
(GSH), the most abundant lens antioxidant, is continuously decreasing in the aging
lens, particularly in the lens nucleus. GSH is usually present in a millimolar concentration
in almost all cell types, and GSH is the most important and abundant non-enzymatic
antioxidant in tissues, cells, and individual compartments. GSH not only serves as
an intracellular redox regulator, but also regulates gene expression, epigenetics,
and amino acid checkpoints. However, the underlying mechanisms of age or disease associated
decline of GSH concentration have never been fully elucidated. My lab is interested
in studying three pathways that regulate lens GSH homeostasis: 1) GSH de novo synthesis; 2) GSH recycling salvage pathway via γ-glutamyltranspeptidase (GGT) and
dipeptidase; 3) GSH transporting.
The pathogenic role of disrupted glutathione homeostasis in amyloid beta pathology
Alzheimer’s disease (AD) is characterized by extra-neuronal b-amyloid (Ab) deposition
in senile plaque and intra-neuronal neurofibrillary tangles. Ab peptides (both 40-
and 42-mer) are produced from the amyloid precursor protein (APP) via the so-called
amyloidogenic pathway. There is compelling evidence that reactive oxygen species (ROS)
are playing a pivotal role in the initiation and development of AD, which is dovetailed
nicely with aging, the primary risk factor of the pathogenesis of AD since ROS is
one of the key characteristics of aging. Growing evidence also points to the emerging
role of ROS in Ab pathology reflected by not only Ab increasing ROS formation but
also ROS promoting the Ab peptide production. Glutathione (GSH), the most abundant
and prevalent antioxidant, is continuously decreasing in the aging brain, and severely
depleted in the AD brain. However, despite these well-documented facts, the pathological
role of disrupted GSH homeostasis in AD remains elusive. We are investigating this
aspect with our hypothesis that disrupted brain GSH homeostasis in aging will promote
the amyloidogenic pathway and Ab production.
The role of a redox modulated Wnt/b-catenin signaling pathway in lens epithelial cell fibrosis and posterior capsule
opacification (PCO)
Cataract surgery is currently the only procedure to treat the vision defect associated
with cataracts. In 2015, over 3.6 million cataract surgical procedures were performed
in the United States, and over 20 million such procedures were performed worldwide.
The opacification of the posterior capsule (PCO), sometimes called secondary cataract
is the most common post-cataract surgery complication. The incidence of PCO rates
and trends vary by the quality of IOLs and the experience of surgeons, typically between
4-45% within 3 years and 6-65% within 5 years for adult patients, while it is almost
100% for children within 2 years of surgical procedure. The mechanisms of PCO formation
remain largely unknown, though the PCO initiation and progression is believed to have
similar pathogenesis as tissue fibrosis, and the LECs postsurgical adaptation is often
regulated by similar signaling pathways as tumorigenesis and tumor progression, such
as epithelial-mesenchymal transition (EMT). Despite distinct differences between LECs-mediated
PCO formation and cancer cells-mediated tumorigenesis, i.e., no mutation is required
in LECs, both cell types do face a hostile growth microenvironment compared to healthy
cells and the sustained stimulation from the microenvironment, i.e., reactive oxygen
species (ROS), is expected to play a pivotal role in cell adaptation, survival, and
invasion. We hypothesize that cataract surgery originates an adverse microenvironment,
i.e., chronic oxidation due to significantly decreased levels of extracellular glutathione
(GSH), which will continuously prompt LECs adaptation, transformation, and PCO formation.
Currently, we are investigating the role of chronic oxidative stress-mediated Wnt/β-catenin
signaling in LECs adaptation and transformation.
Recent Publications:
Srinivasagan R, Fan X, Wang B, Yang S, Monnier VM. Reactive cysteine residues in the oxidative dimerization
and Cu2+ induced aggregation of human γD-crystallin: Implications for age-related
cataract. Biochimica et biophysica acta. Molecular basis of disease. 2018 August 18; 1864(11):3595-3604
Whitson JA, Wilmarth PA, Klimek J, Monnier VM, David L, Fan X. Proteomic analysis of the glutathione-deficient LEGSKO mouse lens reveals activation
of EMT signaling, loss of lens specific markers, and changes in stress response proteins.
Free Radic Biol Med. 2017 Dec;113:84-96. doi: 10.1016/j.freeradbiomed.2017.09.019.
Whitson JA, Zhang X, Medvedovic M, Chen J, Wei Z, Monnier VM, Fan X. Transcriptome of the GSH-Depleted Lens Reveals Changes in Detoxification and EMT
Signaling Genes, Transport Systems, and Lipid Homeostasis. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2666-2684. doi: 10.1167/iovs.16-21398.
Whitson JA, Zhang X, Medvedovic M, Chen J, Wei Z, Monnier VM, Fan X. Transcriptome of the GSH-Depleted Lens Reveals Changes in Detoxification and EMT
Signaling Genes, Transport Systems, and Lipid Homeostasis. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2666-2684. doi: 10.1167/iovs.16-21398.
Feng W, Rosca M, Fan Y, Hu Y, Feng P, Lee HG, Monnier VM, Fan X. Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration.
Hum Mol Genet. 2017 Apr 1;26(7):1376-1390. doi: 10.1093/hmg/ddx040.
Wang B, Hom G, Zhou S, Guo M, Li B, Yang J, Monnier VM, Fan X. The oxidized thiol proteome in aging and cataractous mouse and human lens revealed
by ICAT labeling. Aging Cell. 2017 Apr;16(2):244-261. doi: 10.1111/acel.12548.
Jeremy A Whitson, David R Sell, Michael C Goodman, Vincent M Monnier, Xingjun Fan. Evidence of dual mechanisms of glutathione uptake in the rodent lens: A novel role
for vitreous humor in lens glutathione homeostasis. Invest Ophthalmol Vis Sci. 2016 Jul 1;57(8):3914-25.
L Zhang, Y Li, J Payne, S Srivastava, X Fan, J Fung, X Li, T.S Kern, F Lin, Presence of retinal pericyte-reactive autoantibodies
in diabetic retinopathy patients, Scientific Reports, 2016, Feb 3;6:20341.
Xingjun Fan, Vincent Monnier, Jeremy Whitson, Lens Glutathione Homeostasis: Discrepancies and
gaps in knowledge standing in the way of novel therapeutic approaches. Exp. Eye Res. 2016 Jun 29. pii: S0014-4835(16)30170-1.
Xingjun Fan, Sheng Zhou, Mingfei Guo, Bingbing Li, Benlian Wang, Grant Home, Jing Yang, Vaysburg
Dennis, Vincent M Monnier*. The Disulfidome of the Aging and Cataractous Mouse and
Human Lens. Molecular & Cellular Proteomics, 2015, 14(12):3211-23.
