Honors & Awards
Douglas Johnson Award for Glaucoma Research, BrightFocus Foundation (2013)
The Knights Templar Eye Foundation Travel Fellowship Award, The Knights Templar Eye Foundation/ISER (2016)
Postdoc, Harvard Medical School, Neuroscience (2009)
Ph.D, Weill Medical College of Cornell University, Neuroscience (2006)
Residency, Beijing Friendship Hospital, Ophthalmology (1998)
MD, Beijing Medical University, Medicine (1996)
Current Research and Scholarly Interests
The ultimate goal of the laboratory is to develop efficient therapeutic strategies to achieve CNS neural repair, through promoting neuroprotection, axon regeneration and functional recovery.
More specifically, we study retinal ganglion cell (RGC) and optic nerve in various optic neuropathies including traumatic, glaucomatous and inflammatory optic nerve injuries to fully understand the molecular mechanisms of CNS neurodegeneration and axon regeneration failure.
Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules
JOURNAL OF NEUROSCIENCE
2016; 36 (21): 5891-5903
Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2α-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration.Neuron soma and axon degeneration have distinct molecular mechanisms although they are clearly connected after axon injury. We previously demonstrated that axon injury induces neuronal endoplasmic reticulum (ER) stress and that manipulation of ER stress molecules synergistically promotes neuron cell body survival. Here we investigated the possibility that ER stress also plays a role in axon degeneration and whether ER stress modulation preserves neuronal function in neurodegenerative diseases. Our results suggest that neuronal ER stress is a general mechanism of degeneration for both neuronal cell body and axon, and that therapeutic targeting of ER stress produces significant functional recovery.
View details for DOI 10.1523/JNEUROSCI.3709-15.2016
View details for Web of Science ID 000378345000020
View details for PubMedID 27225776
mTORC1 is necessary but mTORC2 and GSK3ß are inhibitory for AKT3-induced axon regeneration in the central nervous system.
Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.
View details for DOI 10.7554/eLife.14908
View details for PubMedID 27026523
Axon injury induced endoplasmic reticulum stress and neurodegeneration.
Neural regeneration research
2016; 11 (10): 1557–59
Injury to central nervous system axons is a common early characteristic of neurodegenerative diseases. Depending on its location and the type of neuron, axon injury often leads to axon degeneration, retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. Although these sequential events are clearly connected, ample evidence indicates that neuronal soma and axon degenerations are active autonomous processes with distinct molecular mechanisms. By exploiting the anatomical and technical advantages of the retinal ganglion cell (RGC)/optic nerve (ON) system, we demonstrated that inhibition of the PERK-eIF2α-CHOP pathway and activation of the X-box binding protein 1 pathway synergistically protect RGC soma and axon, and preserve visual function, in both acute ON traumatic injury and chronic glaucomatous neuropathy. The autonomous endoplasmic reticulum (ER) stress pathway in neurons has been implicated in several other neurodegenerative diseases. In addition to the emerging role of ER morphology in axon maintenance, we propose that ER stress is a common upstream signal for disturbances in axon integrity, and that it leads to a retrograde signal that can subsequently induce neuronal soma death. Therefore manipulation of the ER stress pathway may be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic.
View details for DOI 10.4103/1673-5374.193225
View details for PubMedID 27904477
- The necessary role of mTORC1 in central nervous system axon regeneration NEURAL REGENERATION RESEARCH 2015; 10 (2): 186-188
The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration
Using mouse optic nerve (ON) crush as a CNS injury model, we and others have found that activation of the mammalian target of rapamycin complex 1 (mTORC1) in mature retinal ganglion cells by deletion of the negative regulators, phosphatase and tensin homologue (PTEN), and tuberous sclerosis 1 promotes ON regeneration. mTORC1 activation inhibits eukaryotic translation initiation factor 4E-binding protein (4E-BP) and activates ribosomal protein S6 kinase 1 (S6K1), both of which stimulate translation. We reasoned that mTORC1's regeneration-promoting effects might be separable from its deleterious effects by differential manipulation of its downstream effectors. Here we show that S6K1 activation, but not 4E-BP inhibition, is sufficient to promote axon regeneration. However, inhibition of 4E-BP is required for PTEN deletion-induced axon regeneration. Both activation and inhibition of S6K1 decrease the effect of PTEN deletion on axon regeneration, implicating a dual role of S6K1 in regulating axon growth.
View details for DOI 10.1038/ncomms6416
View details for Web of Science ID 000345624800037
View details for PubMedID 25382660
Neuronal Endoplasmic Reticulum Stress in Axon Injury and Neurodegeneration
ANNALS OF NEUROLOGY
2013; 74 (6): 768-777
Injuries to central nervous system axons result not only in Wallerian degeneration of the axon distal to the injury, but also in death or atrophy of the axotomized neurons, depending on injury location and neuron type. No method of permanently avoiding these changes has been found, despite extensive knowledge concerning mechanisms of secondary neuronal injury. The autonomous endoplasmic reticulum (ER) stress pathway in neurons has recently been implicated in retrograde neuronal degeneration. In addition to the emerging role of ER morphology in axon maintenance, we propose that ER stress is a common neuronal response to disturbances in axon integrity and a general mechanism for neurodegeneration. Thus, manipulation of the ER stress pathway could have important therapeutic implications for neuroprotection.
View details for DOI 10.1002/ana.24005
View details for Web of Science ID 000329891100007
View details for PubMedID 23955583
Differential Effects of Unfolded Protein Response Pathways on Axon Injury-Induced Death of Retinal Ganglion Cells
2012; 73 (3): 445-452
Loss of retinal ganglion cells (RGCs) accounts for visual function deficits after optic nerve injury, but how axonal insults lead to neuronal death remains elusive. By using an optic nerve crush model that results in the death of the majority of RGCs, we demonstrate that axotomy induces differential activation of distinct pathways of the unfolded protein response in axotomized RGCs. Optic nerve injury provokes a sustained CCAAT/enhancer binding homologous protein (CHOP) upregulation, and deletion of CHOP promotes RGC survival. In contrast, IRE/XBP-1 is only transiently activated, and forced XBP-1 activation dramatically protects RGCs from axon injury-induced death. Importantly, such differential activations of CHOP and XBP-1 and their distinct effects on neuronal cell death are also observed in RGCs with other types of axonal insults, such as vincristine treatment and intraocular pressure elevation, suggesting a new protective strategy for neurodegeneration associated with axonal damage.
View details for DOI 10.1016/j.neuron.2011.11.026
View details for Web of Science ID 000300140600007
View details for PubMedID 22325198
PTEN/mTOR and axon regeneration
2010; 223 (1): 45-50
How axon regeneration is controlled in both PNS and CNS remains elusive. Mechanistic studies of axon growth during development and axon regeneration after injury reveal the PTEN dependent molecular mechanism as a commonality. This pathway could impact the processes occurring in the neuronal soma, such as mTOR-regulated protein translation, and in the axons, such as cytoskeleton assembly. In this review, we will discuss the current understanding of the involvement of these processes in the regulation of axon growth and the potential implication in promoting axon regeneration after injury.
View details for DOI 10.1016/j.expneurol.2009.12.032
View details for Web of Science ID 000277377000007
View details for PubMedID 20079353
Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway
2008; 322 (5903): 963-966
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
View details for DOI 10.1126/science.1161566
View details for Web of Science ID 000260674100053
View details for PubMedID 18988856
Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-alpha and PGE2
JOURNAL OF LEUKOCYTE BIOLOGY
2008; 84 (5): 1353-1360
Maturation of dendritic cells (DCs) by TLR ligands induces expression of IFN-beta and autocrine activation of IFN-inducible Stat1-dependent genes important for DC function. In this study, we analyzed the regulation of STAT signaling during maturation of human DCs by TNF-alpha and PGE2, which induced maturation of human DCs comparably with LPS but did not induce detectable IFN-beta production or Stat1 tyrosine phosphorylation. Consistent with these results, TNF-alpha and PGE2 did not induce Stat1 DNA binding to a standard Stat1-binding oligonucleotide. Instead, TNF-alpha and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF-kappaB and Stat1 target gene IFN regulatory factor 1 (IRF1), which contributes to IFN responses. TNF-alpha and PGE2 induced a complex that bound an oligonucleotide derived from the IRF1 promoter that contains a STAT-binding sequence embedded in a larger palindromic sequence, and this complex was recognized by Stat1 antibodies. These results suggest that TNF-alpha and PGE2 activate STAT-mediated components of human DC maturation by alternative pathways to the IFN-beta-mediated autocrine loop used by TLRs.
View details for DOI 10.1189/jlb.0107040
View details for Web of Science ID 000260016300016
View details for PubMedID 18678606
IFN-gamma and STAT1 arrest monocyte migration and modulate RAC/CDC42 pathways
JOURNAL OF IMMUNOLOGY
2008; 180 (12): 8057-8065
Positive regulation of cell migration by chemotactic factors and downstream signaling pathways has been extensively investigated. In contrast, little is known about factors and mechanisms that induce migration arrest, a process important for retention of cells at inflammatory sites and homeostatic regulation of cell trafficking. In this study, we found that IFN-gamma directly inhibited monocyte migration by suppressing remodeling of the actin cytoskeleton and cell polarization in response to the chemokine CCL2. Inhibition was dependent on STAT1 and downstream genes, whereas STAT3 promoted migration. IFN-gamma altered monocyte responses to CCL2 by modulating the activity of Pyk2, JNK, and the GTPases Rac and Cdc42, and inhibiting CCL2-induced activation of the downstream p21-activated kinase that regulates the cytoskeleton and cell polarization. These results identify a new role for IFN-gamma in arresting monocyte chemotaxis by a mechanism that involves modulation of cytoskeleton remodeling. Crosstalk between Jak-STAT and Rac/Cdc42 GTPase-mediated signaling pathways provides a molecular mechanism by which cytokines can regulate cell migration.
View details for Web of Science ID 000257404600030
View details for PubMedID 18523269
Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages
2007; 68 (3): 156-164
Apoptosis is a critical process in tissue homeostasis and results in immediate removal of the dying cell by professional phagocytes such as macrophages and dendritic cells. Phagocytosis of apoptotic cells actively suppresses production of proinflammatory growth factors and cytokines. Impaired phagocytosis of apoptotic cells has been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study we found that, in addition to suppressing lipopolysaccharide (LPS)-induced production of TNF-alpha and IL-6, phagocytosis of apoptotic cells by macrophages suppressed production of the chemokine CXCL10 that is activated by LPS-induced autocrine-acting type I IFNs. Inhibition of cytokine and chemokine production was not universally affected because LPS-induced production of IL-10 and IL-8 was not significantly affected. Apoptotic cells had minimal effects on LPS-induced activation of NF-kappaB and MAPKs, but induced expression of SOCS proteins and substantially suppressed induction of CXCL10 expression by IFN-alpha. In addition to suppressing LPS responses, apoptotic cells inhibited macrophage responses to another major macrophage activator IFN-gamma by attenuating IFN-gamma-induced STAT1 activation and downstream gene expression. These results identify suppressive effects of apoptotic cells on signal transduction, and extend our understanding of the anti-inflammatory effects of apoptotic cells to include suppression of Jak-STAT signaling.
View details for DOI 10.1016/j.humimm.2006.12.008
View details for Web of Science ID 000245084400002
View details for PubMedID 17349870
- Osteoarthritis and therapy ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH 2006; 55 (3): 493-500
Costimulation of chemokine receptor signaling by matrix metalloproteinase-9 mediates enhanced migration of IFN-alpha dendritic cells
JOURNAL OF IMMUNOLOGY
2006; 176 (10): 6022-6033
Type I IFNs induce differentiation of dendritic cells (DCs) with potent Ag-presenting capacity, termed IFN-alpha DCs, that have been implicated in the pathogenesis of systemic lupus erythematosus. In this study, we found that IFN-alpha DCs exhibit enhanced migration across the extracellular matrix (ECM) in response to chemokines CCL3 and CCL5 that recruit DCs to inflammatory sites, but not the lymphoid-homing chemokine CCL21. IFN-alpha DCs expressed elevated matrix metalloproteinase-9 (MMP-9), which mediated increased migration across ECM. Unexpectedly, MMP-9 and its cell surface receptors CD11b and CD44 were required for enhanced CCL5-induced chemotaxis even in the absence of a matrix barrier. MMP-9, CD11b, and CD44 selectively modulated CCL5-dependent activation of JNK that was required for enhanced chemotactic responses. These results establish the migratory phenotype of IFN-alpha DCs and identify an important role for costimulation of chemotactic responses by synergistic activation of JNK. Thus, cell motility is regulated by integrating signaling inputs from chemokine receptors and molecules such as MMP-9, CD11b, and CD44 that also mediate cell interactions with inflammatory factors and ECM.
View details for Web of Science ID 000237705200041
View details for PubMedID 16670311
IFN-alpha priming results in a gain of proinflammatory function by IL-10: Implications for systemic lupus erythematosus pathogenesis
JOURNAL OF IMMUNOLOGY
2004; 172 (10): 6476-6481
Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN-alpha diminished the ability of IL-10 to suppress TNF-alpha production. IFN-alpha conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-gamma-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN-gamma-inducible protein-10 (CXCL10), and monokine induced by IFN-gamma (CXCL9). IFN-alpha priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma expression in IFN-alpha-primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.
View details for Web of Science ID 000221276900085
View details for PubMedID 15128840
SARA, a FYVE domain protein, affects Rab5-mediated endocytosis
JOURNAL OF CELL SCIENCE
2002; 115 (24): 4755-4763
Rab5, a member of the small GTPase family of proteins, is primarily localized on early endosomes and has been proposed to participate in the regulation of early endosome trafficking. It has been reported that phosphatidylinositol 3-kinases and FYVE domain proteins, such as EEA1, can be recruited onto early endosomes and act as Rab5 effectors. SARA (Smad anchor for receptor activation), also a FYVE domain protein, was initially isolated as a participant in signal transduction from the transforming growth factor beta receptor. Overexpressed SARA has been found on EEA1-positive early endosomes. In this report, we show that endogenous SARA is present on early endosomes and overexpression of SARA causes endosomal enlargement. Functionally, SARA overexpression significantly delays the recycling of transferrin. The transferrin receptor distributed on the cell surfaces was also greatly reduced in cells overexpressing SARA. However, the internalization rate of transferrin is not affected by SARA overexpression. The morphological and functional alterations caused by SARA overexpression resemble those caused by overexpression of Rab5:GTP mutant Rab5Q79L. Finally, all SARA-mediated phenotypic changes can be counteracted by overexpression Rab5:GDP mutant Rab5S34N. These results collectively suggested that SARA plays an important functional role downstream of Rab5-regulated endosomal trafficking.
View details for DOI 10.1242/jcs.00177
View details for Web of Science ID 000180119000005
View details for PubMedID 12432064