Dr Yip, Henry Ka Fun 葉嘉勳
The research in my lab concentrates on the adult central nervous system (eye and spinal cord) and the plasticity and adaptability to environmental stimulation that remains throughout the life of all mammals. The discovery of adult mammalian brain, including human, are capable of producing new nerve cells (stem cells) throughout life has laid the foundation for an emerging new field of biomedical research that holds promise to produce new and replacement cells for repair following disease of injury. We are working to understand how these cells can be induced to become mature functioning nerve cells in the adult eye and spinal cord. We showed that environmental niche and genetic factors regulate the balance between self-renewal and differentiation of these new brain cells and we are studying the underlying cellular and molecular mechanisms that may be harnessed to repair the aged and damaged brain and spinal cord. The objective of our work is to develop models of human development and disease, establish new strategies for discovering and testing drugs, and devise methods of replacing or enhancing eye and spinal cord cells lost or damaged due to neurodegenerative disease or trauma.
Telomerase and neuronal survival. Telomerase is an enzyme consisting of a reverse transcriptase called TERT and an RNA component that adds repeats of a DNA sequence (TTAGGG) to the ends of chromosome, thereby preventing their shortening and cell cycle arrest. Studies showed that suppression of telomerase activity and TERT expression promotes apoptosis of neurons, whereas overexpression of TERT prevents apoptotic cell death. Retinal ganglion cells (RGCs) die by apoptosis after optic nerve (ON) injury in the rodents, whereas no RGC death was observed in goldfish. A possible explanation for the difference in the vulnerability of RGCs to axotomy-induced cell death is the intrinsic capacity of mammalian and fish RGCs to respond to injury. In light of induction and protective role of TERT against various insults in mature tissues, we reasoned that anti-apoptotic effects of TERT could be extended to adult RGCs and contribute to the difference between mammalian and fish RGC in their intrinsic ability to survive after axonal injury. To test this hypothesis, we address the following questions: 1) are there axotomy-induced changes in telomerase gene expression in adult RGCs? Because TERT plays a role in regulating apoptotic cell death, we examined whether axotomy leads to detectable changes in TERT mRNA expression in adult mouse and fish RGCs; 2) is there a difference in TERT expression in fish and rat RGC after axonal injury? And that the difference could account, at least one of the factors, for the difference in the survivability of the injured adult mouse and fish RGCs; 3) does in vivo upregulation of TERT expression extend mouse RGC survival? Finally, what signaling pathways mediate survival triggered by TERT activation in adult mouse RGC in vivo?
Endogenous adult stem cells and spinal cord injury. Astrocytes play important roles in the development and injury response in the central nervous system. Astroglial scar formation is one of the main obstacles to successful axonal regeneration and functional recovery after adult mammalian spinal cord injury. Signaling mechanisms underlying the regulation of astrocyte reaction and scar formation in spinal cord injury are poorly understood, although GSK3/STAT and BMP/Smad signaling pathways have been postulated to promote differentiation of astrocytes. However, the mechanisms that govern astrogliogenesis during the fate determination of neural stem/progenitor cells (NPCs) in the injured spinal cord remain elusive. We have previously reported that BMP/Smad pathway mediates astrocyte differentiation of endogenous NPCs in the injured adult mouse spinal cord. Inhibition of BMP/Smad pathway by Noggin decreases Smad1 activation, but fails to block the activation of STAT3 and the induction of GFAP expression in the injured spinal cord, suggesting that in addition to BMP/Smad pathway, JAK/STAT pathway is also involved in the regulation of astrogliogenesis after spinal cord injury. Lithium has long been used to treat bipolar disorder and has been suggested to have neuroprotective properties. The therapeutic action of lithium is mediated through the inhibition of GSK3 which is known to be an activator of STAT3. Recently, we demonstrated that combined lithium and Noggin treatment has a synergistic effect on promoting generation of neurons and oligodendrocytes, and inhibiting generation of astrocytes by endogenous NPCs derived from the injured adult mouse spinal cord. The purpose of this study is to determine the possible mechanisms responsible for the synergistic effects of combined treatment of lithium and noggin on the inhibition of astroglial scar formation using a mouse model of spinal cord injury. We postulate that STAT3 and Smad1 form a complex with the transcriptional coactivator p300, binds to the response element region of the GFAP promoter and activates GFAP gene, and synergistically induce astrocyte differentiation from the spinal cord-derived NPCs. Thus combined treatment of lithium and Noggin should inhibit the activation of GSK3/STAT and BMP/Smad signaling pathway and suppress astrogliosis. Our study suggests a novel mechanism that by inhibiting the activation of the GSK3/STAT and BMP/Smad signaling pathways promotes the functional conversion of endogenous NPCs in the injured adult spinal cord from an inhibitory astroglial lineage to induced neuronal and oligodendroglial fates leading to tissue repair, axonal regeneration and functional recovery after spinal cord injury.
|Awardees||Award Date||Honours / Awards / Prizes||Category|
|2002-06-01||Accredited Teacher In Higher Education: Staff And Educational Development Association (SEDA), United Kingdom||Teaching Accomplishment|
|2002-06-01||Certificate In Teaching And Learning In Higher Education: Centre For The Advancement of University of Teaching (CAUT), The University of Hong Kong||Teaching Accomplishment|
|2011-04-01||Continuing Professional Development Grant: The University of Hong Kong||Others|
|2011-06-01||University of Hong Kong/China Medical Board Grants 2010/2011: The University of Hong Kong/China Medical Board||Research Achievement|
|1996-05-01||Best Teacher Award: Medical Society, HKUSU||Teaching Accomplishment|
|1998-12-01||University Teaching Fellow: The University of Hong Kong||Teaching Accomplishment|
|Term Period||Position||Professional Societies|
|07/1994 -||Regular Member||Society of Hong Kong Scholars|
|07/1992 -||Regular Member||The Hong Kong Society of Neuroscience|
|07/1982 -||Regular Member||Society for Neuroscience, USA|
|07/1992 -||Regular Member||Association for Research in Vision and Ophthalmology, USA|
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