About My Research
Center/Research Area Affiliations
Biography
At Schepens Eye Research Institute of Mass. Eye and Ear, Dr. Chen studies the molecular mechanisms regulating the stem cell niche and axon regeneration in the adult central nervous system (CNS). Her goal is to apply this knowledge to the development of novel regenerative approaches to treat neural damage and diseases of the eye and brain. Her laboratory was the first to identify novel pathways that control optic nerve regeneration and neural stem cell growth in both the adult brain and retina, which suggests that it may be possible to reactivate dormant regenerative potential as a therapy for neurodegenerative disorders in the CNS and reversing blindness.
Her laboratory subsequently achieved a landmark breakthrough by demonstrating full-length optic nerve regeneration from the eye all the way into the brain in postnatal mice through employing the technique of mouse genetic engineering. They also reported that Müller cells of adult mice possess retinal progenitor cell properties that can be activated by small molecules to generate new photoreceptors. Moreover, Dr. Chen’s laboratory has developed convenient animal models for studying the pathogenesis and drug screening strategies for glaucoma and optic nerve diseases. Aided with these tools, her group is evaluating new approaches for the treatment of glaucoma and optic neuropathy.
Education
MD, Peking University School of Medicine (1986)
PhD, University of Louisville, School of Medicine (1992)
Postgraduate Training
Postdoctoral fellowship, Massachusetts Institute of Technology, Cambridge, MA (1992-1998)
Honors
2008: Outstanding Scientific Achievement Award, the Vision Awards, RP International
2006: Sybil B. Harrington Scholar, Research to Prevent Blindness, New York, NY
- Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc Natl Acad Sci U S A. 2008 Jun 24; 105(25):8778-83.
- Elevated MMP Expression in the MRL Mouse Retina Creates a Permissive Environment for Retinal Regeneration. Invest Ophthalmol Vis Sci. 2008 Apr; 49(4):1686-95.
- Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals. Stem Cells. 2008 May; 26(5):1221-30.
- alpha-Aminoadipate induces progenitor cell properties of Müller glia in adult mice. Invest Ophthalmol Vis Sci. 2008 Mar; 49(3):1142-50.
- Attenuated glial reactions and photoreceptor degeneration after retinal detachment in mice deficient in glial fibrillary acidic protein and vimentin. Invest Ophthalmol Vis Sci. 2007 Jun; 48(6):2760-8.
- Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J Biol Chem. 2007 Jul 06; 282(27):19321-30.
- Characterization of cytokine responses to retinal detachment in rats. Mol Vis. 2006 Aug 07; 12:867-78.
- MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15; 65(22):10413-22.
- Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest Ophthalmol Vis Sci. 2005 Nov; 46(11):4281-7.
- Photoreceptor apoptosis in human retinal detachment. Am J Ophthalmol. 2005 Apr; 139(4):605-10.
- Re-establishing the regenerative potential of central nervous system axons in postnatal mice. J Cell Sci. 2005 Mar 01; 118(Pt 5):863-72.
- Bcl-2 enhances Ca(2+) signaling to support the intrinsic regenerative capacity of CNS axons. EMBO J. 2005 Mar 09; 24(5):1068-78.
- Retinal biopsy techniques for the removal of retinal tissue fragments. Ophthalmic Surg Lasers Imaging. 2005 Jan-Feb; 36(1):76-8.
- Induction of anti-leukemic cytotoxic T lymphocytes by fusion of patient-derived dendritic cells with autologous myeloblasts. Leuk Res. 2004 Dec; 28(12):1303-12.
- Delaying photobleaching and recovering luminescence of a DNA molecular light switch in DNA analysis. Anal Biochem. 2004 Jun 15; 329(2):334-6.
- Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis. Am J Physiol Renal Physiol. 2004 Oct; 287(4):F602-11.
- Response to Quinlan and Nilsson: Astroglia sitting at the controls? Trends Neurosci. 2004 May; 27(5):243-4.
- Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell. 2004 Feb; 5(2):163-75.
- Preventing retinal detachment-associated photoreceptor cell loss in Bax-deficient mice. Invest Ophthalmol Vis Sci. 2004 Feb; 45(2):648-54.
- p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol. 2004 Jan; 24(1):320-9.
- MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec; 2(6):702-6.
- Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene. 2003 Sep 04; 22(38):6107-10.
- Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci. 2003 Aug; 6(8):863-8.
- Immunotherapy of spontaneous mammary carcinoma with fusions of dendritic cells and mucin 1-positive carcinoma cells. Immunology. 2003 Jun; 109(2):300-7.
- Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism. Invest Ophthalmol Vis Sci. 2003 Jan; 44(1):347-54.
- Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12. Blood. 2002 Apr 01; 99(7):2512-7.
- The kinetics of in vivo priming of CD4 and CD8 T cells by dendritic/tumor fusion cells in MUC1-transgenic mice. J Immunol. 2002 Mar 01; 168(5):2111-7.
Show More
Show Less
Functional Restoration of the Optic Nerve after Disease and Injury
We are exploring potential genetic approaches to promote regeneration of the optic nerve and restoration of function.
Military Vision Research Program
We are developing a novel stem cell and bioengineering-based regenerative approach for the treatment of retinal injury and blindness.
Novel Animal Model of Glaucoma
We are developing novel in vitro and in vivo experimental models for the study of glaucoma.
Pathological Changes of Glaucoma in Mice
The research plan proposes a collaborative effort to investigate retinal neuron and immune changes under ocular hypertension in vivo, using genetically engineered or germ-free mice as well as novel imaging technology.
Biological Inquiry into Mechanisms and Neuroprotective Strategy for Neural Trauma
We aim to elucidate the mechanisms underlying neuronal and axon damage in the brain and retina resulted from trauma and ischemia and to develop innovative neuroprotective and regenerative approaches to treat the CNS damage.
Epigenetic Regulation in Retinal Development and Diseases
This project is to define the epigenetic mechanism in retinal neuron development and degeneration for uncovering the novel insights into the contributing factors to congenital retinal dystrophy and unveiling new therapeutic targets.
Current Members of Dr. Dong Feng Chen’s Laboratory
PhD Students
- Karen Chang
- Sam Enayati
- Eric Thee
Postdoctoral Fellows
- Min Ji, MD, PhD
- Yinqian Li, PhD
- Xin Wei, MD, PhD
Instructor
- Kin-Sang Cho, PhD
Alumni
More than 40 trainees have worked in Dr. Chen’s laboratory.
Repairing a Damaged Optic Nerve
The optic nerve is a cable of nerve fibers that carry electrical impulses, containing visual information, from the eye to the brain. In adult mammals, any damage to the optic nerve caused by injury or disease tends to be permanent because the cells that form the optic nerve cannot regenerate or repair themselves. This is why glaucoma and other diseases that involve optic nerve damage, such as optic neuritis and optic nerve trauma, lead to permanent vision loss.
Similarly, nerve fibers in the brain and spinal cord share this common tragic feature of not being able to regenerate. This is most unfortunate, as a capacity for successful nerve regeneration is needed for restoration of visual function. The success of optic nerve regeneration might also open the door to future strategies of eye transplantation.
Scientists around the world are working hard to find a way to regrow the optic nerve. In addition, because of its easy access, the optic nerve has long served as a standard model for the study of spinal cord injury and regeneration in lab animals.
Steps for Optic Nerve Regeneration
Only recently has it become accepted that the failure of the optic nerve to regenerate is not a single-factor event. Successful restoration of vision after optic nerve injury can be divided into five necessary steps:
- First, damaged neurons must be able to stay alive
- Surviving neurons have to be reprogrammed to turn on their growth machinery for nerve re-elongation.
- The re-growing nerve fibers should be able to penetrate injury-generated scar tissue
- The regenerating fibers must overcome growth-inhibitory signals on the path they navigate
- Finally, the fibers also have to be guided back appropriately to their original target to re-form functional connections
In the past, most attempts to promote optic nerve regeneration focused on only one of these steps. Some success in optic nerve regeneration, albeit very limited, was achieved: For example, Aguayo’s group performed a study using growth factors, such as brain-derived nerve growth factor, to support neuron survival (targeting step one). They demonstrated a significant increase in the number of neurons surviving after injury; however, disappointingly, they found little improvement in optic nerve regeneration beyond the site of the injury.
To address step two, Monsul and Hoffman in the Neuro-ophthalmology Laboratory at Johns Hopkins University injected cyclic adenosine monophosphate (cyclic AMP) into the vitreous of mice to boost the neurons’ intrinsic growth potential for nerve re-elongation. They found that cyclic AMP was effective in inducing a small number (less than 1 percent) of nerve fibers to regenerate, but only for a short distance (up to 1 mm), through the crush site.
To target steps three and four, Lehman and colleagues used an enzyme called C3 to enhance neurons’ ability to penetrate glial scars and, at the same time, block nerve-growth inhibitory signals. They found that about 0.5% of nerve fibers regenerated within the injured optic nerve. Similarly, in collaboration with a group at Boston Children’s Hospital (an affiliate of Harvard Medical School), Dr. Chen's lab showed that blocking EGF-receptor signaling suppressed neurons’ responses to glial scars and to nerve-growth inhibitors. As a result, about 0.5% of severed optic nerve fibers regrew past the injury site and elongated up to 2 mm.
Recently, my laboratory achieved an important breakthrough by using combined approaches that simultaneously targeted the first three steps required for optic nerve regeneration. We demonstrated [5] that 40-70% of optic nerve fibers regenerated from the eye all the way into the brain (about 7 mm) in young mice, at ages up to two weeks after birth; this is at a time when nerve-growth inhibitors have already appeared in the mouse brain. We are now planning further studies to overcome the fourth and fifth barriers to optic nerve regeneration, and we hope that functional restoration of sight after optic nerve injury may become possible in the near future, first in mice and then in people.
With recent progress in stem cell research, neural stem cell therapy is emerging as a new approach that may be promising for restoration of sight after optic nerve injury. Attempts have focused on activating dormant stem cells, already present in the eye, to participate in the repair process in response to injury. In addition, it may be possible to harvest and transplant donor stem cells into the eyes of patients whose optic nerves have been injured, to replace the neurons that have been lost or to provide a permissive environment for nerve regrowth. Although these studies are still in their infancy, the field is progressing rapidly and may soon turn the stem cell approach into a viable therapy.